LU82880A1 - 6 BETA-HYDROXYALKYLPENICILLANIC ACID DERIVATIVES, THEIR PRODUCTION PROCESS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

/ / I v! "4 * 1 i *;! 'I One of the most well-known and widely used classes of antibacterial agents is the class of ß-lactam antibiotics. These compounds are characterized in that they comprise a nucleus consisting of a condensed 2-azetidinone (ß-lactam) ring, either with a thiazolidine ring or with a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually designated by the generic term - penicillins, while when the nucleus 10 contains a dihydrothiazine cycle, they are called cephalosporins. Representative examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethyl-penicillin (penicillin V), ampicillin and carbenicil-15; representative examples of common cephalosporins are cephalothin, cephalexin 'and cefazolin.

However, despite the wide use and great success of ß-lactam antibiotics as interesting chemotherapeutic agents, their main disadvantage is that some of their representatives are not active against certain microorganisms. It is believed that in many cases this resistance of a particular microorganism to a given ß-lactam antibiotic is due to the fact that the microorganism develops a ß-lactamase. The latter substances are enzymes that split the ß-lactam cycle of penicillins and cephalosporins into products that are devoid of antibacterial activity. However, certain substances * have the ability to inhibit ß-lactamases, and when a ß-lactamase inhibitor * is used in combination with a penicillin or a cephalosporin, it can increase or promote the antibacterial efficacy of penicillin or cephalosporin against certain beta-lactamase producing microorganisms. It is considered that there is an improvement in antibacterial efficacy when the antibacterial activity of a combination between a substance which inhibits a ß-lactamase and an antibiotic of the i 2 / i * * ß-lactam type is significantly greater than the sum antibacterial activities of the individual components against microorganisms producing ß-lactamase.

The present invention provides a series of 5 ββ-hydroxyalkylpenicillanic acids and their esters which are readily hydrolysable in vivo, which are potent inhibitors of microbial ß-lactamases and which improve the efficacy of ß-lactam antibiotics. The invention further relates to benzyl 6β-hydroxyalkylpenicillanates, these 10 esters being chemical intermediate compounds useful for obtaining the corresponding acids.

Pharmaceutical compositions containing

Cf penicillanic acids substituted in position 6β and their readily hydrolyzable esters mentioned above, with certain antibiotics of the β-lactam type, as well as a method for increasing the effectiveness of certain antibiotics of the β-lactam type in combination with the Penicillanic acids substituted in the 6β position and their readily hydrolyzable esters mentioned above also fall within the scope of the present invention.

Di Ninno et al. Described in J. Org. Chem., 42, 2960 (1977) the synthesis of 6β-hydroxyalkylpenicillanic acids and the corresponding benzyl esters, which constitute, respectively, potent antibacterial agents and useful intermediates.

6-Ethylpenicillanic acid and its sulfoxide are described as antibiotics in US Patent No. 4,123,539.

* 30 6a-hydroxypenicillanic acid and its esters 1 * were prepared from 6-diazopenicillanic acid and * from the corresponding esters [J. Org. Chem., 39, 1444 (1974) J.

U.S. Patent No. 4,143,046 discloses antibacterial agents which are sulfonyloxypenicillanic acids substituted in the 6β position.

The compounds of the invention correspond to the formulas: / 3 fr

H H

c = s CH, H? ° 2 'CH, S ^ I f pca, R "- | —f'S'Y ^ CH, X — Ί — t, —A-1. ,, 3 0. C02R1 0 '"2 * 1

5 1 and IX

or to the formula of a corresponding pharmaceutically acceptable base salt, formulas in which R is an alkylsulfonyloxymethyl group having 1 to 4 carbon atoms in the alkyl group, a phenylsulfonyloxy-methyl group, substituted phenylsulfonyloxymethyl whose

iM

substituent is a methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl radical or an 1-hydroxy-3-phenyl-propyl group; is a benzyl group, a hydrogen atom or an ester-forming residue readily hydrolyzable in vivo; and r2 is a group of the formula: p3 R4-CH- wherein Rg is a sulfo group, hydrogen, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkanoyl group having 2 to 18 carbon atoms, a benzoyl group, a substituted benzoyl group the substituent of which is an amino, methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl radical, an alkylsulfonyl group having 1 to 4 carbon atoms, a substituted phenylsulfonyl or phenyl-sulfonyl group whose substituent is a methyl, methoxy, fluoro, chloro, bromo or trifluoro-methyl radical; and R4 is a hydrogen atom, an alkyl group 4 having 1 to 4 carbon atoms, a phenyl, benzyl, pyridyl or 8-phenethyl group.

V

A preferred group of β-lactamase inhibitors includes the compounds of formula II in which R- ^ and R ^ are each a hydrogen atom. Particularly preferred in this group are the compounds in which Rg is hydrogen or an acetyl, stearoyl or benzoyl group.

A second group of preferred compounds corresponding to formula II comprises the compounds in which R · ^ and Rg are each a hydrogen atom and R4 is a ► 4 ί alkyl group having 1 to 4 carbon atoms. Particularly appreciated in this group are the compounds in which R 1 is a methyl group.

A third group of preferred compounds of formula I includes those in which R.sup.3 is a hydrogen atom. Particularly preferred in this group are the compounds in which R is a methylsulfonyloxy-methyl, p-toluenesulfonyloxymethyl or 1-hydroxy-3-phenyl-propyl group.

The present invention also relates to a pharmaceutical composition useful for the treatment of bacterial infections in mammals, which composition comprises a pharmaceutically acceptable carrier, a β-lactam antibiotic and a compound of the formulas: 15 n HH HH ° 2 CH,: o CH,:: S 3 r ^ CH3 co2r5 s' co2e5

20 III and - IV

(or a pharmaceutically acceptable base salt of this compound), formulas in which R is an alkylsulfonyloxymethyl group having 1 to 4 carbon atoms in its alkyl group, a phenylsulfonyloxymethyl group, a substituted phenylsulfonyloxymethyl group the substituent of which is a methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl radical or an 1-hydroxy-3-phenyl-propyl group; R2 is a group of formula: ·? OR, I 3 "R4-CH- wherein R3 is a sulfo group, hydrogen, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkanoyl group having 2 to 18 carbon atoms, a benzoyl group, substituted benzoyl whose substituent is an amino, methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl radical, an alkylsulfonyl group having 1 to 4 carbon atoms, a substituted phenylsulfonyl or phenylsulfonyl group r 5 fwt substituted whose substituent is a methyl radical, methoxy, fluoro, chloro, bromo or trifluoromethyl; R4 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl, pyridyl, benzyl or 8-5 phenethyl group? and is hydrogen or an easily forming hydrolyzable ester residue in vivo.

Preferred compounds are the compounds of formulas III and IV in which R5 is hydrogen or a residue forming an ester which is easily hydrolysable in vivo, chosen from an alkanoyloxymethyl residue having 3 to 6 carbon atoms, 1- (alkanoyloxy ) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having 5 to 8 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 atoms Carbon, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and γ-butyrolacton-4-yl, and the 8-lactam antibiotics are chosen from penicillins and cephalosporins. Particularly preferred are compounds of formula IV wherein R 1 and R 5 are each hydrogen and R 3 is hydrogen or an acetyl, stearoyl or benzoyl group. A particularly appreciated compound is also that in which R ^ and Rj. each represents a hydrogen atom and R ^ is a methyl group. Particularly preferred are compounds of formula III wherein R is methylsulfonyl-oxymethyl, p-toluenesulfonyloxymethyl or 1-hydroxy-3-phenylpropyl.

The invention also relates to a method for * increasing the efficacy of an 8-lactam * antibiotic in a mammal, which method comprises co-administering to the mammal an amount which increases the effectiveness of the 8-lactam type antibiotic of a compound of formulas: • HH HH ° 2: c CH- ï: ς. CH- „p a *« _ 3 R-3 35 K -η ^ 2 Y f * CH, J-N- \ 3 h-N- ° C ° 2S5 0 'C02S5

III IV

) 6 "or a pharmaceutically acceptable base salt of this compound, in which formulas R is an alkylsulfonyloxymethyl group having 1 to 4 carbon atoms in the alkyl group, a substituted phenylsulfonyloxymethyl group, 5-phenylsulfonyloxymethyl group of which the substituent is a methyl, methoxy, fluoro, chloro, bromo or trifluoro-methyl radical or an 1-hydroxy-3-phenylpropyl group; R2 is a group of formula: ° -R3

ίο I

R4-CH- wherein R3 is a sulfo group, hydrogen, an alkoxycarbonyl group having 2 to 4 carbon atoms, alkanoyl having 2 to 18 carbon atoms, benzoyl, substituted benzoyl the substituent of which is an amino radical , methyl, methoxy, fluoro, chloro, bromo or trifluoromethyl, an alkylsulfonyl group having 1 to 4 carbon atoms, phenylsulfonyl or substituted phenylsulfonyl the substituent of which is a methyl, methoxy, fluoro, chloro, bromo or trifuoro-methyl radical and R ^ is hydrogen, an alkyl group having 1 to 4 carbon atoms, a phenyl, benzyl, pyridyl or β-phenethyl group; and R5 is hydrogen or a residue forming an easily hydrolysable ester in vivo.

Preferred compounds are the compounds of formulas III and IV in which Rg is hydrogen or a residue forming an easily hydrolysable ester in vivo chosen from an alkanoyloxymethyl group having 3 to 6 carbon atoms, a group 1- (alkanoyloxy) ethyl having 4 to 7 carbon atoms, a 1-methyl-1- (alkanoyloxy) - group, ethyl having 5 to 8 carbon atoms, an alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, a group 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, a 1-methyl-1- (alkoxycarbonyloxy) ethyl group having 5 to 8 carbon atoms, a 3-phthalidyl, 4-crotono-35 lactonyl or y-butyrolacton-4 group -yle and ß-lactam antibiotics are chosen from penicillins and cephalosporins. Particularly preferred compounds correspond to formula IV in which R4 and R5 are each a hydrogen atom and R3 is a hydrogen atom or 9 7 ♦ -m * an acetyl, stearoyl or benzoyl group. In this class, the compound in which Rg and R ,, are each a hydrogen atom and R ^ is a methyl group is also particularly appreciated.

Particularly preferred compounds of formula III are those in which R is methylsulfonyloxymethyl, p-toluenesulfonyloxymethyl or 1-hydroxy-3-phenylpropyl.

The definition of the ester-forming residues mentioned above covers any ester which is easily / hydrolyzed in a mammal. Particularly appreciated are residues forming an easily hydrolyzable ester in vivo chosen from alkanoyloxymethyl residues having 3 to 6 carbon atoms, 1- (alkanoyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having 5 to 8 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, 3 -phthalidyl, 4-crotonolactonyl and y-butyrolacton-4-yl.

The preferred 8-lactams whose antibiotic activity is favored by the 6 8-hydroxyalkylpenicillanic acid sulfones of the present invention are chosen from the following compounds: 6- (2-phenylacetamido) penicillanic acid, 6- (2- phenoxyacetamido) penicillanic acid 6- (2-phenylpropionamido) penicillanic acid 6- (D-2-amino-2-phenylacetamido) penicillanic acid ^ acid 6- (D-2-amino-2- [4-hydroxyphenylJacetamido) -? 30 penicillanic, = 6- (D-2-amino-2 - (. 1,4-cyclohexadienyl Jacetamido) acid - penicillanic, 6- (1-aminocyclohexanecarboxamido) penicillanic acid, 6- (2-carboxy-2-phenylacetamido acid) penicillanic, 6- (2-carboxy-2 - (. 3-thienylJacetamido) acid penicillanic, 6- (D-2- (4-ethylpiperazine-2,3-dione-1-carboxamidoJ-2-phenylacetamido) acid, penicillanic 6- (D-2- [4-hydroxy-1,5-naphthyridine-3-carboxamidoJ-2-phenylacetamido) penicillanic acid, fr 8 "6- (D-2-sulfo-2-phenylacetamido) penicillanic acid, acid 6 - (D-2-sulfamino-2-phenylacetamido) penicillanic acid 6- (D-2- [imidazolidine-2-one-1-carboxamidoJ-2-phenyl- "acetamido) penicillanic acid 6 (D-2 - [3-methylsulfonylimidazolidine-2-one-l-carboxamido J-2-phenylacetamido) penicillanic acid 6- ((.hexahydro-1H-azepin-1-yl Jmethyleneamino) -penicillanic, 6- (2-phenylacetamido) penicillanate acetoxymethyl, 10 6- (D-2-amino-2-phenylacetamido) acetoxy methyl penicillanate, 6- (D-2-amino-2- (4-hydroxyphenylJacetamido) penicillanate acetoxymethyl, pivaloyloxymethyl penicillanate 6- (2-phenylacetamido), pivaloyloxymethyl penicillanate 6- (D-2-amino-2-phenylacetamido) 6- (D-2-amino-2- [4-hydroxyphenylacetamido) penicillanate , 6- (2-phenylacetamido) penicillanate ethyl- (ethoxycarbonyloxy) -20 ethyl, 6- (D-2-amino-2-phenylacetamido) penicillanate 1- (ethoxycarbonyloxy) ethyl, 6- (D-2- 1- (ethoxycarbonyloxy) ethyl amino-2- (4-hydroxyphenylJacetamido) penicillanate, 3-phthalidyl penicillanate 6- (2-phenylacetamido) 3-phthalidyl penicillanate 6- (D-2-amino-2-phenylacetamido) , 6- (D-2-amino-2 - (. 4-hydroxyphenyl Jacetamido) 3-phthalidyl penicillanate, * 6- (2-phenoxycarbonyl-2-phenylacetamido) penicillanic acid, * 30 6- (2-tolyloxycarbonyl- 2-phenylacetamido) - penicillanic acid 6- (2- (5-indanyloxycarbonylJ-2-phenylacetamido) -penicillanic acid 6- (2-phenoxycarbonyl-2- (3-thienylJacetamido) -35 penicillanic acid 6- (2 -tolyloxycarbonyl-2 - (. 3-thienyl Jacétamido) -pénicillanique , 6- (2- (5-indanyloxycarbonyl J-2 - (. 3-thienyl Jacétamido) -penicillanic acid), ê 9 6- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) acid - penicillanic acid 7- (2 - (. 2-thienyl) acetamido) cephalosporanic acid 7- (2- (l-tetrazolylJacetamido-3- (2- (5-methyl-l, 3,4-5 thiadiazolyl] thiomethyl) -3-deacetoxymethyl cephalosporanic acid 7- (D-2-formyloxy-2-phenylacetamido) -3- (5- (1-methyl-tetrazolylJthiomethyl) -3-deacetoxymethyl cephalosporanic acid 7- (D-2-amino-2-phenylacetamido ) deacetoxy-cephalosporanic, 7-alpha-methoxy-7- (2- (2-thienylJacetamido) -3-a carbamoyloxymethyl-3-deacetoxymethyl cephalosporanic acid, 7- (2-cyanacetamido) cephalosporanic acid, 7- (D-2 acid) -hydroxy-2-phenylacetamido) -3- (5- (1-methyltetra-zolyl) thiomethyl) -3-deacetoxymethylcephalosporanic acid 7- (D-2-amino-2-p-hydroxyphenylacetamido) deacetoxy-cephalosporanic, acid 7 - (2- (4-pyridylthioJacetamido) cephalosporanic acid 7- (D-2-amino-2- (1,4-cyclohexadienylJacetamido) -cephalosporanic acid 7- (D-2-amino-2-phenylacetamido) cephalosporanic acid 7- (D - (-) - alpha- (4-ethyl-2,3-dioxo-1-piperazine-carboxamido) -alpha- (4- hydroxyphenyl) acetamido J-3 - ((1-methyl-1,2,3,4-tetrazol-5-yl) thiomethylJ-3-cephem-4-carboxylic acid 7- (D-2-amino-2-phenylacetamido ) -3-chloro-3-cephem-4-25 carboxylic acid 7- (2- (2-amino-4-thiazolyl) -2- (methoximino) acetamidoJ-cephalosporanic, (6R, 7R-3-carbamoyloxymethyl-7 (2Z) -2-methoxyimino (fur-2-yl) -, acetamido-ceph-3-em-4-carboxylateJ, "acid 7- (2- (2-aminothiazol-4-yl) acetamidoJ-3- ( ((1,2-- dimethyl-amino-ethyl) -1H-tetrazol-5-ylJthiomethylJceph-3-em-4-carboxylic acid, and their pharmaceutically acceptable salts.

The inhibitors of $ -lactamase of the present invention are advantageously prepared from benzyl 6,6-di-bromopenicillanate. The condensation of a suitably selected aldehyde with the enolate formed by reacting benzyl 6,6-dibromopenicillanate with an organo-metallic reactant, according to the method taught by Di Ninno et al in J. Org. Chem., £ 2, 2960 (1977), results in the formation of a benzyl 6-bromo-6-hydroxyalkylpenicillanate, the initial intermediate compound leading to the production of the products of the present invention.

The product of this initial condensation is formed of diastereoisomeric mixtures due to the presence of two asymmetry centers, one in position 6 of the penam nucleus and the second at the level of the carbon atom in position 6 in the chain, as shown below:

V

H

Br *: ... CH3

Hy <Hf T ”cg3 15 R u ® K4 0 C02CH2C6H5

As is obvious to those skilled in the art, there is only one of these two centers of asymmetry in this intermediate when R4 is a hydrogen atom.

The substituents at position 6 are in the a or ß configuration and the respective configuration is indicated in the structural formula by a dashed line link or by a solid line link. The stereochemical configuration of the side chain substituent is designated by the letters (R) or (S) (Cahn et al., Experientia, 12, 81 (1956). The assignment of the configuration is based on magnetic resonance spectroscopy. nuclear.

* 30 Benzyl 6,6-dibromopenicillanate in a solvent inert to the reaction at a temperature of -20 to -78 ° C is treated with approximately one equivalent of tert-butyl lithium chloride or tertiary butyl magnesium chloride. The resulting enolate is then treated with the suitably selected aldehyde and, after a short reaction period, the reaction mixture is quenched and the product is isolated by conventional means.

11 * * The addition of zinc chloride to an enolate solution before the addition of the aldehyde clearly influences the stereochemistry of the condensation product. Consequently, under these conditions, a strong prepon-5 of the configuration (S) is obtained in the side chain.

When diethyl zinc is used as the initial organometallic reagent, a preponderance of the configuration (R) is obtained in the side chain of the product v.

The initial reaction is carried out in an anhydrous solvent inert to the reaction, which dissolves the reactants to an appreciable extent without reacting appreciably with the reactants or the products under the reaction conditions. It is preferred that these solvents have boiling points and freezing points compatible with reaction temperatures. These solvents or their mixtures include aromatic solvents such as toluene and solvents of the type of ethers such as tetrahydrofuran and diethyl ether.

The molar ratio of the starting penicillanate and the organometallic reagent is not critical to the process. The use of a slight excess of organometallic compound, up to 10% above an equimolar amount, facilitates the completion of the reaction and does not cause severe problems in the isolation of the desired product under the purified form.

The reaction mixture can be effectively kept away from moisture by using a nitrogen or argon atmosphere.

41 30 The reaction time naturally depends on the; concentration, reaction temperature and reactivity of the starting reactants. When the reaction is carried out in the preferred temperature range of -60 to -78 ° C, the reaction time for the formation of the enolate is about 30 to 45 minutes. The reaction time for the formation of the intermediate product from the above-mentioned enolate and aldehyde is about 30 to 60 minutes.

12 ψ ♦

When the reaction is complete, the product is isolated by conventional procedures and the diastereoisomeric mixture can be separated by column chromatography. However, the nature of the following reaction, which is the elimination of the bromo substituent at position 6, dispenses with said separation of the a and β spines at position C-6.

The treatment of benzyl 6-bromo-6-hydroxyalkyl-penicillanate resulting from the first reaction with tri-n-butyltin hydride leads to the formation of a benzyl 6-hydroxyalkylpenicillanate of which group 6 i hydroxyalkyl is in the ß configuration. This result is independent of the conformation of the substituents at position 6 of the starting reactants. Thus, the 6a-bromo-63-hydroxyalkyl esters and the 63-15 bromo-6a-hydroxyalkyl esters all give, by treatment with tri-n-butyltin hydride, the same 63-hydroxy- ester. alkyl as the main product, assuming that all other structural parameters of the compounds are the same.

The reaction is carried out in an inert solvent which dissolves the reactants to an appreciable extent without reacting to a significant degree with them or with the product under the reaction conditions. It is further preferable that this solvent is an aprotic solvent, immiscible with water, and that it has a boiling point and a freezing point compatible with the reaction temperatures. Such solvents or mixtures of solvents include preferred solvents such as benzene and toluene.

The duration of the reaction depends on the concentration, the reaction temperature and the reactivity of the reactants. When the reaction is carried out at the preferred temperature, i.e. the reflux temperature of the solvent, it is usually completed in a period of about 4 to 5 hours.

The molar ratio of reactants is not critical to the process. Usually, an excess of tin hydride is used and the excess that is used can go up to 100% beyond an equimolar amount.

13 * * *

When the reaction is complete, the solvent is removed and the residue is triturated with hexane to remove the organic tin compound formed as a by-product. The intermediate product can be purified and the isomers can be separated by column chromatography.

The oxidation of benzyl 63- (S) and (R) -hydroxyalkyl penicillanate resulting in corresponding sulfones of formula II in which is a benzyl group is carried out conventionally by means of an organic acid peroxide, for example a peroxycarboxylic acid such as m-chloroperbenzoic acid. The reaction is carried out by treatment of the suitably chosen benzyl 63- (R) or (S) -hydroxyalkylpenicillanate with about 2 to about 4 equivalents and preferably about 2.2 equivalents of the oxidant in an inert solvent vis- with respect to the reaction. Examples of solvents include chlorinated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane.

The oxidant and the substrate are initially brought into contact with a solvent at a temperature of 0 to 5 ° C. The temperature is allowed to rise to room temperature. The reaction time is approximately 3 to 6 hours.

During the isolation of the sulfones, which constitute useful intermediate compounds, the solvent is removed and the residue is partitioned between water and a water-immiscible solvent such as ethyl acetate. The pH of the mixture of water and organic solvent is adjusted to 7.0 and any excess of peroxide is decomposed by the addition of sodium bisulfite. The intermediate product, which is contained in the organic phase, is isolated and purified by conventional procedures.

The biologically active products of the present invention, of formulas I and II in which R ^ is a hydrogen atom, are prepared by debenzylation of the corresponding benzyl esters. Consequently, the suitably chosen benzyl ester is added to a suspension of a 5% palladium-based prehydrogenated catalyst fixed on calcium carbonate in a 50% solution of 14% methanol and water. The hydrogenolysis is carried out at ambient temperature and is usually carried out under a pressure of 315 to 350 kPa. Under these conditions, the reaction is usually completed in a period of 30 to 60 minutes. The filtration of the spent catalyst followed by the removal of the solvent by lyophilization makes it possible to isolate the calcium salt. Acidification of the filtrate, after removal of the catalyst, followed by extraction with a water immiscible solvent such as ethyl acetate, makes it possible to isolate the free acid, in which is an atom. hydrogen.

Alternatively, the compounds of formula II in which is a hydrogen atom can also be prepared by the same series of reactions as that described above, but in a different order of succession. For example, the benzyl 6-bromo-6-hydroxyalkyl-penicillanates initially formed can be oxidized as described above and the oxidation can be followed by the removal of the substituent 6-bromo by tri-n- hydride. butyl tin and debenzylation.

Compounds of the present invention of formula II wherein R3 is an alkanoyl group are prepared by acylation of the desired benzyl 60-hydroxyalkylpenicillanate sulfone, followed by hydrogenolysis of the benzyl ester to form the compounds of formula II wherein R3 has the definition given and R- ^ is a hydrogen atom.

The acylation is carried out by bringing the desired penicillanate sulfone into contact with an equimolar amount of the desired acid halide, plus an excess of up to 10 to 20%, in a solvent inert to the * 30 reaction, such as methylene chloride. A tertiary amine added in molar amounts corresponding to the acid halide plays the role of acceptor vis-à-vis the hydrogen halide formed.

The acylation is carried out at a reaction temperature of about 0 to 5 ° C and requires a reaction time of about 20 to 30 minutes. The intermediate product is obtained by removing the solvent and treating the resulting residue with a mixture of water and ethyl acetate and the organic phase is evaporated to give the desired materials.

The formation of the final products, that is to say the compounds of formula II in which R3 is an alkanoyl group and is a hydrogen atom, is carried out by debenzylation under the conditions which have been defined above.

The compounds of the present invention, of formula II in which R3 is a benzoyl group, the indicated substituted benzoyl group or the indicated alkoxycarbonyl group, are all prepared in a manner analogous to the preparation of the compounds in which is an alkanoyl group , and the process involves the initial acylation of the suitable benzyl 63-hydroxyalkylpenicillanate sulfone followed by removal of the benzyl portion of the ester.

The compounds of the present invention of formula I, in which R is the substituted alkylsulfonyloxymethyl, phenylsulfonyloxymethyl or phenylsulfonyloxymethyl group, indicated and of formula II, in which R3 is the substituted alkylsulfonyl group, phenylsulfonyl or phenylsulfonyl, indicated are almost all advantageously prepared by initial acylation of the desired benzyl 63-hydroxyalkyl penicillanate with an approximately equimolar amount of the suitably selected sulfonyl chloride, using pyridine as solvent, a reaction temperature of 0 ° and a reaction time of about 2 to 3 hours. The product is isolated by deactivating the reaction mixture with water, then extracting and purifying it.

The second reaction in the series involves the enz debenzylation of the intermediate ester by means of hydrogen and 5% palladium fixed on calcium carbonate, a process which has already been described.

The final step in obtaining the compounds of formula II consists in oxidizing the 63-sulfonyloxyalkyl-penicillanic acids with potassium permanganate in a mixture of water and methylene chloride at ambient temperatures: · 16 * · * and a pH of 6 to 6.4. After the reaction, which lasts about 45 to 60 minutes, the pH is adjusted to 1.5 and the product is isolated from the organic phase.

The synthesis of the compounds of formula II in which is a sulfo group is carried out by reaction of the suitably chosen benzyl 63-hydroxyalkylpenicillanate sulfone with the sulfuric anhydride and pyridine complex in dimethylformamide at room temperature for 45 to 60 minutes.

The product, which is isolated in the form of the pyridinium salt, is debenzylated with hydrogen and with 5% palladium * fixed on calcium carbonate, as indicated in the foregoing.

When is a residue forming an easily hydrolyzable ester in vivo in a compound of formula I or II, it is a group hypothetically derived from an alcohol of formula R ^ -OH, so that the group COOR ^ d 'Such a compound of formula I or II represents an ester group. In addition, R ^ is of such a nature that the group COOR ^ is easily cleaved in vivo by liberating a free carboxy group (COOH). This amounts to saying that R · ^ is a group of the type which, when a compound of formula I or II, in which R ^ is a residue forming an ester which is easily hydrolysed in vivo, is exposed to blood or to a tissue of a mammal, the compound of formula I or II, in which R 1 is a hydrogen atom, is readily produced. R- groups are known in the field of penicillins. In most cases, they improve the absorption characteristics of the penicillin compound. In addition, R ^ must be of such a nature that it confers pharmaceutically acceptable properties on a compound of formula I or II and that it releases * pharmaceutically acceptable fragments when it is split in vivo.

As indicated above, the R 1 groups are known and are readily identified by those skilled in the art of penicillins, as taught in German Federal Patent Application No. 2,517,316. Representative examples of R ^ groups are 3- ψ 17 phthalidyl, 4-crotonolactonyl, y-butyrolacton-4-yl, alkanoyloxyalkyl and alkoxycarbonyloxyalkyle groups. Preferred groups, however, are alkanoyloxymethyl groups having 3 to 6 carbon atoms, 1- (alkanoyloxy) -5 ethyl groups having 4 to 7 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl groups having 5 to 8 carbon atoms, alkoxycarbonyloxymethyl groups having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl groups having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyl-10 oxy) ethyl groups having 5 a 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and y-butyrolacton-4-yl groups.

Compounds of formula I or II, in which R 1 is a residue forming an easily hydrolysable ester in vivo, can be prepared directly from the compound of formula I or II, in which R 1 is a hydrogen atom, by esterification . The particular method which one chooses naturally depends on the precise structure of the residue forming an ester, but a preferred method is easily chosen by a person skilled in the art. If R ^ is chosen from 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, alkanoyloxyalkyl and alkoxycarbonyloxyalkyle groups, they can be prepared by alkylation of the compound of formula I or II, in which R ^ is hydrogen, with a 3-phthalidyl halide, a 4-crotono-lactonyl halide, a y-butyrolacton-4-yl halide, an alkanoyloxyalkyl halide or an alkoxycarbonyloxyalkyl halide. The term "halide" is used to denote chlorine, bromine and iodine derivatives. The reaction is advantageously carried out by dissolving a * 30 salt of the compound of formula I or II, in which R ^ is a hydrogen atom, in a suitable polar organic solvent * such as Ν, Ν-dimethylformamide, then addition about one molar equivalent of the halide. When the reaction is essentially complete, the product is isolated by conventional techniques. It suffices simply to dilute the reaction medium with an excess of water, then to extract the product in an organic solvent immiscible with water and then to recover the product by evaporation of the solvent. Salts of the starting material which are commonly used are alkali metal salts such as sodium and potassium salts and tertiary amine salts such as triethylamine, N-ethylpiperidine, Ν, Ν-dimethylaniline and 5 N-methylmorpholine. The reaction is carried out at a temperature in the range of about 0 to 50 ° C and usually at a temperature of about 0 to 25 ° C. The time required for the completion of the reaction varies in accordance with various factors such as the concentration of reactants and the reactivity of the reactants. Consequently, if we consider the halogenated compound, iodide reacts faster than bromide which, in turn, reacts faster than chloride. In fact, it is sometimes advantageous, when using a chlorinated compound, to add up to one molar equivalent of an alkali metal iodide. This has the effect of speeding up the reaction. In view of the above factors, reaction times from 1 to about 24 hours are commonly used.

The compounds of formulas I and II, in which 20 is a hydrogen atom, are acidic and form salts with basic agents. These salts are considered to fall within the scope of the present invention. These salts can be prepared by conventional techniques, for example by contacting the acidic and basic components, usually in a molar ratio of 1: 1, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then collected by filtration, by precipitation with a non-solvent, followed by filtration, - evaporation of the solvent or, in the case of aqueous solutions, lyophilization, as the case may be. Basic agents which are advantageously used in the formation of salts belong to the organic type and to the inorganic type and include ammonia, organic amines, hydroxides, carbonates, bicarbonates, alkali metal hydrides and alcoholates as well as hydroxides, carbonates, hydrides and alcoholates of alkaline earth metals. Representative examples of these bases are primary amines such as n-propylamine, n- "19" butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethyl-5 piperidine, N-methylmorpholine and 1,5-diazabicyclo- (.4.3.0Jnon-5-ene; hydroxides such as sodium hydroxide, 1 ' potassium hydroxide, ammonium hydroxide and barium hydroxide, alcoholates such as sodium ethylate and potassium ethylate; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids, such as 2-ethyl-15 sodium hexanoate.

Preferred salts of the compounds of formulas I and II, in which R ^ is a hydrogen atom, are the sodium, potassium and triethylamine salts.

. As noted above, the compounds of formulas I and II, in which R- ^ is a hydrogen atom or a residue forming an easily hydrolysable ester in vivo, are potent inhibitors of microbial 3-lactamases, and they improve the antibacterial efficacy of 3-lactam antibiotics (penicillins and cephalo-sporins) against numerous microorganisms, in particular those which develop a 3-lactamase. The ability of the compounds of formulas I or II to increase the efficacy of a 3-lactam antibiotic can be assessed from experiments in which the minimum inhibitory concentration * of an antibiotic alone and of a compound of formula I or II alone is measured. These minimum inhibitory concentrations are then compared with the minimum inhibitory concentration values obtained with a given antibiotic in combination with the compound of formula I or II. When the antibacterial activity of the association is significantly greater than the activities of the individual compounds allow to predict, it is considered that there is an improvement in the activity. The values of ψ c 20 "minimum inhibitory concentration of combinations of substances were measured by the method described by Barry and Sabath in the" Manual of Clinical Microbiology ", edited by Lenette, Spaulding and Truant, second edition, 1974, 5 American Society for Microbiology.

The compounds of formulas I and II, in which R 2 is a hydrogen atom or a residue forming an ester which is easily hydrolysable in vivo, improve the antibacterial efficacy of 3-lactam antibiotics in vivo. 10 This means that they reduce the amount of antibiotic that is needed to protect mice from an otherwise deadly inoculum of certain 3-lactamase producing bacteria.

The ability of the compounds of formulas I and II, in which R ^ is a hydrogen atom or a residue forming an ester which is easily hydrolysable in vivo, to improve the efficacy of a 3-lactam antibiotic against bacteria producing 3-lactamase, makes them interesting for use by co-administration with antibiotics of the 3-lactam type in the treatment of bacterial infections in mammals, in particular in humans. In the treatment of a bacterial infection, said compound of formula I or II can be combined with an antibiotic of the 3-lactam type and the two agents can thus be administered simultaneously. Alternatively, the compound of formula I or II can be administered as a separate agent during treatment with an antibiotic of the 3-lactam type. In some cases, it is advantageous to pretreat the subject with the compound of formula I or II before initiating treatment with a 3-lactam antibiotic.

When a compound of formula I or II is used, in which Rx is a hydrogen atom or an easily hydrolysable ester group in vivo to improve the efficacy of a 3-lactam antibiotic, a mixture of the compound I or II with the 3-lactam type antibiotic, preferably in formulation with conventional pharmaceutical carriers or diluents. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a 3-lactam antibiotic and a compound of formula I or II, in which is a hydrogen atom or an easily hydrolyzable ester of this compound , normally contains from about 5 to about 80% by weight of the pharmaceutically acceptable carrier 5.

When the compounds of formula I or II are used, in which R ^ is a hydrogen atom or an ester group which is easily hydrolysable in vivo in combination with another antibiotic of the 3-lactam type, these compounds can be administered orally or parenterally, that is, intramuscularly, subcutaneously or intraperitoneally. Although the attending physician ultimately decides the dosage to be used in a human, the ratio of daily doses of the compound of formula I or II to the β-lactam antibiotic is normally within the range from about 1: 3 to 3: 1. In addition, when the compounds of formula I or II are used in combination with another 3-lactam antibiotic, the daily oral dose of each component is normally in the range of about 10 to about 200 mg / kg of body weight and the daily parenteral dose of each component is normally between about 10 and about 400 mg / kg of body weight. However, these figures are given by way of illustration only and in some cases it may be necessary to use doses which deviate from these limits.

Representative examples of 3-lactam antibiotics with which the compound of formula I or II and its easily hydrolyzable esters in vivo can be co-administered are indicated below: 6- (2-phenylacetamido) penicillanic acid , 6- (2-phenoxyacetamido) penicillanic acid, 6- (2-phenylpropionamido) penicillanic acid, 6- (D-2-amino-2-phenylacetamido) penicillanic acid, 6- (D-2-amino-2- acid (.4-hydroxyphenyl Jacetamido) -penicillanic acid 6- (D-2-amino-2 - (. 1,4-cyclohexadienyl Jacetamido) -penicillanic! * 22 i 6- (1-aminocyclohexanecarboxamido) penicillanic acid 6 - (2-carboxy-2-phenylacetamido) penicillanic acid 6- (2-carboxy-2 - (. 3-thienyl) acetaraido) penicillanic acid 6- (D-2- [4-ethylpiperazine-2,3-dione -l-carboxamidoj-5 2-phenylacetaraido) penicillanic acid 6- (D-2 - (. 4-hydroxy-l, 5-naphthyridine-3-carboxamidoJ- 2- phenylacetamido) penicillanic acid 6- (D-2- sulfo-2-phenylacetamido) penicillanic acid 6- (D-2-sulfamino-2-phenylacetamido) p enicillanic acid 6- (D-2- (imidazolidine-2-one-l-carboxamidoJ-2-phenyl-acetamido) penicillanic acid 6- (D-2- [3-methylsulfonylimidazolidine-2-one-l-carboxamido J-2-phenylacetamido) penicillanic acid 6 - ([hexahydro-1H-azepin-l-ylJmethylene-amino) -15 penicillanic, 6- (2-phenylacetamido) acetoxymethyl penicillanate, 6- (D-2-amino -2-phenylacetamido) acetoxy-methyl penicillanate, 6- (D-2-amino-2 - (. 4-hydroxyphenylJacetamido) acetoxymethyl penicillanate, 6- (2-phenylacetamido) pivaloyloxymethyl penidillanate, 6- (D -2-amino-2-phenylacetamido) pivaloyloxymethyl penicillanate, 6- (D-2-amino-2- [4-hydroxyphenylJacetamido) pivaloyloxymethyl penicillanate, 6- (2-phenylacetamido) penicillanate 1- (ethoxycarbonyloxy) -ethyl , 6- (D-2-amino-2-phenylacetamido) penicillanate ethyl- (ethoxy- „carbonyloxy) ethyl, * 30 6- (D-2-amino-2- [4-hydroxyphenyljacetamido) penicillanate 1- (ethoxycarbonyloxy ) ethyl, '6- (2-phenylacetamido) 3-phthalidyl penicillanate, 6- (D-2-amino-2-phenylacetam ido) 3-phthalidyl penicillanate, 35 6- (D-2-amino-2 - (. 4-hydroxyphenyl jacetamido) 3-phthalidyl penicillanate, 6- (2-phenoxycarbonyl-2-phenylacetamido) penicillanic acid, 6- (2-tolyloxycarbonyl-2-phenylacetamido) -penicillanic, 23 c acid 6- (2- [5-indanyloxycarbonylJ-2-phenylacetamido) -r penicillanic, 6- (2-phenoxycarbonyl-2- [3-thienylJacetamido) -penicillanic acid , 5 acid 6 (2-tolyloxycarbonyl-2- (3-thienyl Jacétamido) -pénicillanique, acid 6- (2 - (. 5-indanyloxycarbonylJ-2- [3-thienyl Jacétamido) -pénicillanique, acid 6- (2,2 -dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -10 penicillanic acid 7- (2 - (. 2-thienyl Jacétamido) cephalosporanic acid 7- (2 - (. l-tetrazolylJacetamido-3- (2 - (5-methyl-1,3,4-thiadiazolyljthiomethyl) -3-deacetoxymethylcephalosporanic acid 7- (D-2-formyloxy-2-phenylacetamido) -3- (5- [1-methyl-15 tetrazolyljthiomethyl) -3- deacetoxymethylcephalosporanic, 7- (D-2-amino-2-phenylacetamido) acid deacetoxy-cephalosporanic, 7-alpha-methoxy-7- (2- (. 2-thienyl jacetamido) -3-carbamoyloxymethyl-3 “deacetoxymethyl cephalosporanic acid 7- (2 ~ cyanacetamido) cephalosporanic, acid 7- (D-2-hydroxy-2-phenylacetamido) -3“ (5- [l- * methyl -tetrazolyljthiomethyl) -3-deacetoxymethylcephalosporanic acid 7- (D-2-amino-2-p-hydroxyphenylacetamido) deacetoxy-cephalosporanic acid 7- (2 - (. 4-pyridylthioJacetamido) cephalosporanic 2- -amino-2- [1,4-cyclohexadienylJacetamido) -cephalosporanic acid 7- (D-2-amino-2-phenylacetamido) cephalosporanic, i. acid 7 ”[d - (-) - alpha- (4-ethyl- 2,3-dioxo-1-piperazine- * 30 carboxamido) -alpha- [4-hydroxyphenyl) acetamidoJ-3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethylJ-3- cephem-4- 'carboxylic acid 7- (D-2-amino-2-phenylacetamido) -3-chloro-3-cephem-4-carboxylic acid 7- [2- (2-amino-4-thiazolyl) acid -2- (methoximino) acetamidoJ-cephalosporanic, (.6R, 7R-3-carbamoyloxymethyl-7 (2Z) -2-methoxyimino- (fur-2-yl) acetamido-ceph-3-em-4-carboxylate J, * * 24 acid 7 - (. 2- (2-aminothiazol-4-yl) acetamido J — 3— C ((1,2-dimethylaminoethyl) -1H-tetrazol-5-ylJthiomethyl) ceph-3-em-4-carboxylic # and a pharmaceutically acceptable salt of these compounds.

As is obvious to those skilled in the art, some of the above 3-lactam compounds are effective when administered orally or parenterally, while others are only effective when administered administered parenterally. When compounds of formula I, in which is a hydrogen atom or an easily hydrolysable ester group in vivo, must be used at the same time as a 3-lactam antibiotic, that is to say in a mixture with it, and that the latter is effective only by parenteral administration, a combined formulation is used which is suitable for parenteral administration. When the compounds of formula I, in which is a hydrogen atom or an ester group and a 3-lactam antibiotic which is only effective orally or parenterally, must be used simultaneously (as a mixture) suitable combinations for oral or parenteral administration can be prepared. In addition, preparations of the compounds of formula I can be administered orally while administering another antibiotic of the 3-lactam type parenterally; similarly, it is also possible to administer preparations of the compounds of formula I parenterally, while administering the other antibiotic of the 3-lactam type orally.

The following examples are given by way of illustration only. The nuclear magnetic resonance (NMR) spectra were measured at 60 MHz on * solutions in deuterochloroform (CDClg), perdeutero-dimethylsulfoxide (DMSO-dg) or deuterium oxide (D20) r unless otherwise specified, and peak positions were expressed in parts per million (ppm) relative to tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate used as a reference standard. The following abbreviations have been used for the 25? peaks: s, singlet; d, doublet; t, triplet; q, »quadruplet; m, multiplet.

EXAMPLE 1

Sulfone decides 6β-hydroxymethylpenicillanic 5 A. Benzyl 6-bromo-6-hydroxymethylpenicillanate

A solution of 44.9 g of benzyl 6f6-dibromopenicil-lanate in 600 ml of anhydrous tetrahydrofuran is cooled to -78 ° C and 56.4 ml of tert-butyl chloride = magnesium are added dropwise with stirring. energetic in a nitrogen atmosphere, the temperature being at the same time maintained at -60 ° C. After stirring for 30 minutes at -78 ° C, the solution is treated with gaseous formaldehyde in a stream of nitrogen until 5 molar equivalents have been added. The reaction mixture was quenched at -78 ° C by the addition of 5.7 ml of acetic acid, dropwise, over a period of 25 minutes. The reaction solution is allowed to warm to room temperature and concentrated in vacuo. 200 ml of water and 200 ml of ethyl acetate are added to the residue. The organic phase is separated and the aqueous phase is extracted again with ethyl acetate. The organic phases are combined, washed successively with 200 ml of water, 200 ml of 5% aqueous sodium bicarbonate solution and 200 ml of brine and dehydrated over magnesium sulfate. Removal of the solvent under reduced pressure gives 38.2 g of the desired product, epimeric at the C-6 atom.

B. benzyl 68-hydroxymethylpenicillanate

A solution containing 10 g of benzyl 6-bromo-6-hydroxy- * methylphenicillanate, 6.9 ml of tri-n-butyltin hydride and traces of azo-bis-isobutyronitrile in 200 ml of benzene. The reaction mixture is cooled and concentrated in vacuo. The residue is triturated with hexane and chromatographed on silica gel using a mixture of toluene and ethyl acetate (2: 1) as the eluent to give 7.5 g of the product.

"26 C. Benzyl 63-hydroxymethylpenicillanate sulfone

11.8 g of m-chloroperbenzoic acid are added to a solution of 7.5 g of benzyl 63-hydroxymethylpenicillanate in 600 ml of methylene chloride cooled to 0-5 5 ° C. The solution is then allowed to warm to room temperature and stirred for 5 hours. The solvent is removed in vacuo and the residue is partitioned between 200 ml of water and 200 ml of ethyl acetate. The pH of the mixture is adjusted to 7 by the addition of a saturated solution of sodium bicarbonate and enough sodium bisulfite is added for the peroxide (starch-iodide) detection test to be negative. The phases are separated and the aqueous phase is washed with ethyl acetate. The organic phase and the washing liquors are combined, washed successively with water, a 5% solution of sodium bicarbonate and brine and dried over magnesium sulphate. By removing the solvent under reduced pressure, a foam is obtained which gives, by chromatography on silica gel (chloroform-ethyl acetate 20: 3), 3.5 g of the desired intermediate product.

D. Calcium 6β-hydroxymethylpenicillanate sulfone

3.5 g of 5% palladium fixed on calcium carbonate are added to 30 ml of a 1: 1 mixture of water and methanol and the catalyst is prehydrogenated under pressure of 329 kPa in a hydrogenation apparatus. 3.5 g of benzyl 6β-hydroxymethylpenicillanate sulfone in 10 ml of methanol and 20 ml of tetrahydrofuran are added to the resulting catalyst and the mixture is shaken in an atmosphere of hydrogen under pressure of 336 kPa for 30 30 minutes. The catalyst is filtered using a filtration aid and the filtrate is concentrated in vacuo. The aqueous residue is extracted with 2 times 100 ml of ethyl acetate and lyophilized to obtain 3.0 g of the desired product in the form of the calcium salt.

35 The NMR spectrum (CDCI 3 - free acid) shows absorptions at 1.49 (s, 3H), 1.6 (s, 3H), 4.1 (m, 3H), 4.32 (s, 1H) and 4.9 (d, 1H, J = 4Hz) ppm.

"27 EXAMPLE 2

Benzyl 6ß- [l- (S) -hydroxyethylJpenicillanic acid sulfone A. 6ß-bromo-6a- [l- (S) -hydroxyethyljpenicillanate

15 ml of 5-tert-butyl lithium in pentane are added dropwise to a stirred solution of 9 g of benzyl 6,6-dibromopenicillanate in 200 ml of anhydrous toluene at -78 ° C under an argon atmosphere. The greenish-yellow solution is stirred for 15 minutes at -78 ° C, then 10 ml of a 1 M solution of anhydrous zinc chloride in tetrahydrofuran are added. The mixture is stirred for 45 minutes at -78 ° C, then 5 ml of acetaldehyde is added, while the temperature is maintained at -78 ° C. After stirring for a further 1 hour, the reaction mixture is quenched with 5 ml of acetic acid in 50 ml of ether at -78 ° C and allowed to warm to room temperature. The toluene is removed in vacuo and the residue is partitioned between water and ethyl acetate. The organic phase is separated and the aqueous phase is extracted with 2 times 100 ml of ethyl acetate. The combined organic phases are washed with a 5% aqueous solution of sodium bicarbonate, then with a saturated solution of sodium chloride. They are then dried over magnesium sulfate and concentrated to give an oil which, by chromatography on silica gel with elution with a 10: 2 mixture of toluene and ethyl acetate, gives 3.5 g of benzyl 6a-bromo-penicillanate and 3.9 g of the desired product. An analytical sample purified by recrystallization from ether melts at 124-125 ° C.

• 30 The NMR spectrum (CDCl ^) shows absorptions at 1.42 (s, 3H), 1.45 (d, 3H, J = 6Hz), 1.67 (s, 3H), 2.55 (s, '1H), 4.3 (q, 1H, J = 6Hz), 4.6 (s, 1H), 5.3 (s, 2H), 5.5 (s, 1H) and 7.4 (s, 5H) ppm.

B. 68 - (. 1- (S) -hydroxyethyl benzyl penicillanate 35 1.1 g of 5% palladium fixed on calcium carbonate are added to 20 ml of a mixture of methanol and water at 1: 1 and the resulting mixture is hydrogenated for 20 minutes under a pressure of 329 kPa. 1.1 g of 63-bromo-6a - (- l- (s) -hydroxyethylJpenicil-benzyl lanate) are added to the resulting black suspension 28 4 and continued hydrogenation under pressure of 329 kPa for 30 minutes, the spent catalyst is removed by filtration and the filtrate is concentrated under reduced pressure, the pH of the aqueous residue is adjusted to 8 and the residue is extracted with methylene chloride. organic is separated, dried over magnesium sulphate and evaporated to give an oil The residual oil is then chromo-tographed on 150 g of silica gel, elution being carried out with a mixture of chloroform and acetate ethyl at 10: 1. Fractions 23 to 33 are combined and evaporated to dryness, giving 148 mg of the desired product.

The NMR spectrum (CDCl3) shows absorptions at 1.35 (d, 3H), 1.4 (s, 3H), 1.58 (s, 3H), 2.5 15 (m, 1H), 3, 45 (dd, 1H, J = 10, 4Hz), 4.2 (m, 1H), 4.38 (s, 1H), 5.13 (s, 2H), 5.38 (d, 1H, J = 4Hz) and 7.33 (s, 5H) ppm.

C. Benzyl 6ß-Ll- (S) -hydroxyethyljpenicillanate sulfone

223 mg of m-chloro-20 perbenzoic acid are added in portions to a solution of 148 mg of 6 3 - (. 1- (S) “hydroxyethyl benzyl penicillanate in 20 ml of methylene chloride, 0-5 The resulting reaction mixture is kept under stirring at room temperature for about 18 hours, the undissolved solids are filtered and the filtrate is evaporated to dryness under reduced pressure, the residue is partitioned between a 5% aqueous solution. sodium bicarbonate and ethyl acetate. Sodium bisulfite is added to the mixture with vigorous stirring until a search for peroxide (starch-iodide) is negative. The organic phase is then separated and the aqueous phase is extracted with an additional quantity of ethyl acetate The combined organic phases are rinsed successively with saturated sodium bicarbonate solution and brine, then they are dried over magnesium sulphate. By hunting the solva nt under vacuum, 160 mg of the product are obtained in the form of an oil.

The NMR spectrum (CDC13) shows absorptions at 1.27 (s, 3H), 1.35 (d, 3H, J = 6Hz), 1.5 (s, 3H), 6 29 3.2 (m, 1H), 3.85 (dd, 1H, J = ll, 5Hz), 4.53 (s, 1H), 4.77 (m, 1H), 4.77 (d, 1H, J = 5Hz), 5 , 28 (ABq, 2H, J = 12Hz) and 7.43 (s, 5H) ppm.

D. Acid sulfone 6 8 - (, l- (S) -hydroxyethyl] penicillanic 5 A suspension of 160 mg of 5% palladium fixed on calcium carbonate in 20 ml is prehydrogenated under pressure of 329 kPa for 20 minutes 1: 1 mixture of methanol and water 160 mg of benzyl 68 - (. 1- (S) -hydroxyethyl) penicillanate sulfone is added to the resulting suspension and the hydrogenation is continued for 1 hour under pressure of 357 kPa. The spent catalyst is filtered and the pH of the filtrate is adjusted to 8. After the aqueous phase has been extracted with ethyl acetate, the pH is adjusted to 1.8 and acetate d fresh ethyl is added, the ethyl acetate phase is separated, dried over magnesium sulfate and concentrated to give 90 mg of an oil, the oil then crystallizes to give a white solid which melts at 160 -161.5 ° C when decomposing.

The NMR spectrum (CDClg - DMSO-dg) shows absorptions at 1.2 (d, 3H, J = 6Hz), 1.42 (s, 3H), 1.52 (s, 3H), 3.80 (dd, 1H, J = 10.5Hz), 4.28 (s, 1H), 4.5 (m, 1H) and 5.20 (d, 1H, J = 5Hz) ppm.

EXAMPLE 3

Benzyl 6ß- [1- (R) -hydroxyethylJ penicillanic acid sulfone 6ß-bromo-6α - (.l- (R) -hydroxyethyl ·) benzyl penicillinate

70 ml of diethyl zinc, also cooled to -78 ° C, are slowly added to 50 ml of toluene cooled to -78 ° C.

Then 45 g of benzyl 6,6-dibromopenicillanate in 250 ml of toluene are added to the reaction mixture over a period of 30 to 45 minutes. After stirring for 1 hour in the refrigerator, 17. ml of acetaldehyde is added to the reaction mixture and stirring is continued for 1 hour. The reaction mixture is quenched by the addition of 11.5 ml of acetic acid in 100 ml of diethyl ether. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature. An equal volume of water and ethyl acetate is added to the reaction mixture which is kept under stirring for 30 minutes. The organic phase is then separated and washed successively with 3 times 75 ml of water, 3 times 75 ml of a saturated solution of sodium bicarbonate and 1 time 100 ml of saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and evaporated in vacuo to give an oil which is chromatographed on 500 g of silica gel using a mixture of chloroform and 10% ethyl acetate as eluent : 1. Fractions 13 to 29 are combined and evaporated to dryness, giving 20 g of the crude intermediate product which is recrystallized from a mixture of diethyl ether and hexane, giving 12.7 g of melting substance at 109 ° -110 ° C. . The isolated material also contains benzyl 6-bromo-6a- [1- (S) -hydroxyethylJ penicillanate.

Benzyl 6ß- [1- (R) -hydroxyethylJ penicillanate

A solution of 1.0 g of benzyl 6ß-bromo-βa- [l- (R) -hydroxyethylJpenicillanate and 1.4 ml of tri-n-butyl tin hydride in 35 ml is refluxed for 40 minutes. of benzene under a nitrogen atmosphere. The reaction mixture is then cooled to room temperature and the solvent is removed under reduced pressure. The residue is triturated several times with hexane. It is chromatographed on 100 g of silica gel using a 20: 1 mixture of chloroform and ethyl acetate as eluent. Fractions 82 to 109 are combined and evaporated to obtain 750 ml of the desired product.

The NMR spectrum (CDClg) shows absorptions 1.18 (d, 3H, J = 6Hz), 1.38 (s, 3H), 1.62 (s, 3H), 2.6 (m, 1H), 3.45 (dd, 1H, J = 9.4Hz), 4.2 (m, 1H), 4.43 (s, f 30 1H), 5.16 (s, 2H), 5.33 (d, 1H, J = 4Hz) and 7.33 (s, 5H) ppm.

C. Sulfone of benzyl 63- (. 1- (R) -hydroxyethyl Jpenicillanate *

A mixture of 335 mg of benzyl 6 3- [1- (R) -35 hydroxyethyl J penicillanate and 507 mg of m-chloroperbenzoic acid in 50 ml of methylene chloride is stirred for about 18 hours at room temperature. The solids are filtered and the solvent is removed from the filtrate. The residue is partitioned between 50 ml of water and 50 ml of ethyl acetate. Sodium bisulfite is added per dl 31 portions to the mixture with stirring until all the peroxide has been destroyed, which is demonstrated by obtaining a negative test for starch and iodide. . The organic phase is separated, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is used in the next step without further purification.

D. 6 6 - (, l- (R) -hydroxyethyl] penicillanic acid sulfone

A suspension of 1.78 g of 5% palladium fixed on 10 of calcium carbonate in 40 ml of mixture of methanol and water at 1: 1 is hydrogenated for 20 minutes at a pressure of 350 kPa. 1.67 g of benzyl 6ß- [1- (R) -hydroxyethyljpenicillanate sulfone are added to the resulting suspension and the hydrogenation is continued under pressure of 350 kPa for 1 hour. The methanol is removed under reduced pressure and the aqueous residue is extracted with ethyl acetate. The aqueous phase is acidified to a pH of 2 and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to give 1.0 g of a white solid which melts at 182-183 ° C as it decomposes .

The NMR spectrum (DMSO-dg) shows absorptions at 1.15 (d, 3H, J = 6Hz), 1.37 (s, 3H), 1.47 (s, 3H), 3.87 (dd, 1H, J = 10.5Hz), 4.28 (s, 1H), 4.5 (m, 1H), 5.11 (d, 1H, J = 5Hz) and 5.5 (m, 4H).

EXAMPLE 4

Benzyl 6ß- [1- (S) -hydroxyethyljpenicillanic acid sulfone A. Benzyl 6β-bromo-6a- [1- (S) -hydroxyethylJ-penicillanate sulfone - 14.7 g of 6ß-bromo- 6a- [1- (S) -hydroxyethyl benzyl penicillanate (Example 2A) and 17.8 g * of m-chloroperbenzoic acid in 500 ml of methylene chloride maintained at 5 ° C. under a nitrogen atmosphere and the resulting reaction mixture with stirring for about 18 hours. Another 200 mg of the peracid are added and stirring is continued for a further 2.5 hours. The reaction mixture is filtered and the filtrate is concentrated to obtain a white solid. An equal volume of mixture of water and ethyl acetate is added to residue 32 and the pH is adjusted to 7.4 by addition of a saturated sodium bicarbonate solution. The organic phase is separated, added to fresh water and the pH is adjusted to 8.2 by adding a saturated solution of sodium bicarbonate. The ethyl acetate phase is rinsed with 3 times 400 ml of saturated sodium bicarbonate solution, then with a solution of sodium chloride. The organic phase is separated, dried over magnesium sulfate and evaporated to obtain 18.2 g of an oil.

10 The NMR spectrum (CDCl 4) shows absorptions at 1.28 (s, 3H), 1.43 (d, 3H, J = 6 Hz), 1.55 (s, 3H), 4.2 (q, 1H, J = 6Hz), 4.57 (s, 1H), 4.85 (s, 1H), 5.23 (ABq, 2H, J = 12Hz) and 7.38 (s, 5H) ppm.

B. Benzyl 6ß- [1- (S) -hydroxyethylpenicillanate sulfone

0.52 ml of tri-n-butyltin hydride is added to a solution of 740 mg of benzyl 6ß-bromo-6a- [1- (S) -hydroxyethyljpenicillanate sulfone in 10 ml of benzene under one atmosphere of nitrogen and the resulting mixture is heated at reflux for 3 hours. The benzene is removed in vacuo and the residue is triturated with hexane. The hexane is poured in by decantation and the residue is used in the next step, without further purification.

C. 6β- [1- (S) -hydroxyethylpenicillanic acid sulfone 1 g of 5% palladium fixed on calcium carbonate is reduced beforehand in 20 ml of water with hydrogen under pressure of 350 kPa. The crude benzyl 63 - (. 1- (S) -hydroxyethylJ-penicillanate sulfone in 20 ml of methanol from> 4B from Example 4B is added to the resulting suspension and the hydrogenation is continued for 1 hour under 350 kPa. Another 500 mg of catalyst is added and the reaction is continued for 45 minutes. The spent catalyst is filtered and the filtrate is extracted with twice 50 ml of ethyl acetate. A layer is deposited on the aqueous phase. of fresh ethyl acetate and the pH is adjusted to 1.5 The organic phase is separated and the aqueous phase is extracted with 7 times 100 ml of ethyl acetate The acid phases of acetate extraction ethyl are combined, washed with sodium chloride solution, dried over magnesium sulfate and concentrated to dryness in vacuo giving 230 mg of residue.

The NMR spectrum is identical to that of the product prepared in D in Example 2.

5 EXAMPLE 5

Sulfone acid 6 $ - [1- (R) -hydroxyethyljpenicillanic A. Sulfone 6 ß-bromo-6a - (.l- (R) -hydroxyethyl J benzicillanate

3.6 g of m-chloroperbenzoic acid are added to a solution of 2.9 g of benzyl 6ß-bromo-6a - (. 1- (R) -hydroxyethyl) -penicillanate (Example 3A) in 100 ml of methylene chloride cooled to 0-5 ° C and the resulting reaction mixture is kept under stirring at room temperature for about 16 hours. The solvent is removed under reduced pressure and the residue is dissolved in an equal volume of mixture of water and ethyl acetate. The pH of the mixture is adjusted to 7.4 by addition of a saturated sodium bicarbonate solution and the organic phase is separated. The organic phase is rinsed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to obtain. an oil which crystallizes; 4.0 g.

The NMR spectrum (CDC13) shows absorptions at 1.25 (s, 3H), 1.28 (d, 3H, J = 6Hz), 1.5 (s, 3H), 2.9 (m, 1H ), 3.7 (dd, 1H, J = 10.5Hz), 4.43 (s, 1H), 4.6 (m, 1H), 4.57 (d, 1H, J = 5Hz), 5, 17 (ABq, 2H, J = 12Hz) and 7.32 (s, 5H) ppm.

B. Benzyl 6ß- [1- (R) -hydroxyethylpenicillanate sulfone A 3.0 g mixture of 3- 3- bromo-6a- [1-] sulfone is refluxed for 30 minutes under a nitrogen atmosphere. (R) -benzyl hydroxyethylpenicillanate and 2.9 ml of tri-n-butyltin hydride in 100 ml of benzene. The solvent is removed in vacuo and the residue is extracted several times with hexane. The residual material is chromographed on 250 g of silica gel and 1.67 g of the desired product are obtained, which is used in the next step.

34 C. Acid sulfone 60 - (, 1- (R) -hydroxyethyljpenicillanic

1.7 g of 5% palladium fixed on calcium carbonate in 40 ml of 50% methanol and water are predreduced for 20 minutes under pressure of 350 kPa. To the resulting suspension is added 1.67 g of sulfon of benzyl 6 0 - (. 1- (R) -hydroxyethylJ penicillanate and the hydrogenation is continued for 1 hour. The catalyst is filtered and the methanol is removed from the filtrate under The aqueous residue is extracted with water, then the pH of the aqueous phase is adjusted to 2.0, the acidified aqueous phase is extracted several times with ethyl acetate and the extracts are washed. combined with saturated sodium chloride solution, then dried over magnesium sulphate Removal of the solvent gives 1.0 g of the product which is indistinguishable from that which was prepared in D in Example 3. EXAMPLE 6

Starting from benzyl 6,6-dibromopenicillanate and suitably selected aldehyde and using the procedures of Example 2, the sulfones of 6 3 - (. 1- (S) -hydroxyalkyl Jpenicillanic acid) are prepared. following: acid sulfone 6 3 - (. 1- (S) -hydroxypropyl Jpenicillanic; acid sulfone 63 - (. 1- (S) -hydroxy-n-butylJpenicillanic; sulfone acid 63 - (. 1- (S) -hydroxy-2-methylpropyl J-25 penicillanic; acid sulfone 6 3 - (. 1- (S) -hydroxy-n-pentyl Jpenicillanic; acid sulfone 6 3 - (. 1- (S) -hydroxy-2-methyl-n-butylJ-penicillanic; acid sulfone 63-il- (S) -hydroxy-3-methyl-n-butylJ-? penicillanic; and acid sulfone 63 - (. l- (S) -hydroxy-2,2-dimethylpropylJ-penicillanic.

EXAMPLE 7

Following the procedures of Example 3 and starting from the desired aldehyde and benzyl 6,6-dibromopenicil-lanate, the following compounds are prepared: acid sulfone 63 (.- (. 1- ( R) -hydroxypropyl Jpenicillanic acid sulfone 63 - (. 1- (R) -hydroxy-2-methylpropylJ-penicillanic acid; sulfone 63-ll- (R) -hydroxy-n-pentylJ penicillanic acid sulfone; 6 3 - (.l- (R) -hydroxy-2-methyl-n-butylJ-penicillanic acid; acid sulfone 6 3 - (. 1- (R) -hydroxy-3-methyl-n-butyl J- 5 penicillanic; and acid sulfone 6 3 - (. 1- (R) -hydroxy-2,2-dimethylpropyl] -penicillanic.

EXAMPLE 8

Starting from suitably chosen 6-bromo-6 - (. 1-hydroxyalkyl] penicil-10-benzylanate and following the procedures of Examples 4 and 5, the following compounds 63 are prepared: 15? HH Ç ° 2 ^ CH3 R4-ch ÂfcÜ-Ύ s Ch3

J- N -L

O 'CO-H

20 i _ _1_; CH3CH2- (S); ch3ch2- (R) 25 CH3 (CH2) 2- (R) ch3 (ch2) 3- (S) ch3 (ch2) 3- (R) CH3CH (CH3) - (S) CH3CH (CH3) CH2- (S) '? 30 (CH3) 3C- (R) (CH3) 3C- (S) 35 ^ 36 f * ί EXAMPLE 9

6B- [1- (S) -hydroxybenzylJpénicillanigue acid sulfone and

Acid sulfone 68 - (, 1- (R) -hydroxybenzyl Jpénicillanigue 5 A. 6a-bromo-6 ß- [1- (R) and (S) -hydroxybenzyljpénicillanates

14 ml of tert-butyl lithium cooled to -67 ° C are added to a solution of 9.0 g of benzyl 6,6-dibromopenicillanate in 200 ml of anhydrous toluene cooled to -78 ° C = 10 and kept under argon atmosphere. After shaking at

refrigerator for 45 minutes, 2 ml of benzaldehyde are added and the reaction mixture is stirred for 1 hour. A solution of 1.2 ml of acetic acid in 50 ml of diethyl ether is then added over a period of 10 minutes and the mixture is stirred at -78 ° C

during 30 minutes. 100 ml of water and 100 ml of diethyl ether are added and the mixture is stirred at room temperature for 30 minutes. The organic phase is separated and the aqueous phase is washed with ether. The organic phase and the ether washing liquors are combined and washed successively with 1 time 50 ml of water, 2 times 50 ml of saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated to give 10.3 g of an oil.

The residual material is chromatographed on 450 g of silica gel, the eluent used being a mixture of chloroform and ethyl acetate at 20: 1. Fractions 71-101 are pooled and concentrated to give 1.97 g of the product as a semi-solid.

B. 6ß— L1— (R) -benzylhydroxybenzyljpenicillanate and 6 ~ 0- [l- (S) -hydroxybenzylbenzylpenicillanate

A solution of 1.9 g of 6a-bromo-6 8 - (. 1- (R) and (S) -hydroxybenzylPenzicillanates and 1.1 ml of sorting hydride is refluxed for 3.5 hours. -n-butyl-tin in 30 ml of anhydrous benzene under a nitrogen atmosphere. Another 1.0 ml of hydride is added and heating is continued under reflux for approximately 16 hours. The benzene is removed in vacuo and diluted the residue with hexane. The hexane is poured in by decantation and the 850 mg of residual oil is chromatographed on 100 g of silica gel, using a mixture of chloroform and 20% ethyl acetate as eluent. : 3, Fractions 20 to 34 are combined and the solvent is removed to obtain 495 mg of benzyl 6 3 - (. 1- (R) -hydroxy-benzyljpénicillanate.

The NMR spectrum (CDClg) shows absorptions at 1.42 (sf 3H), 1.67 (s, 3H), 3.2 (m, 1H), 3.9 (dd, 1H, J = 4, 10Hz ), 4.42 (s, 1H), 5.2 (s, 2H), 5.2 (m, 1H), 10 5.4 (d, 1H, J = 4Hz) and 7.35 (m, 10H ) ppm.

Fractions 35 to 58 are combined and concentrated under vacuum to obtain 380 mg of benzyl 6 3- [1- (S) -hydroxy-benzylJpenicillanate "

The NMR spectrum (CDCl3) shows absorptions at 1.33 (s, 3H), 1.67 (s, 3H),. 3.4 (m, 1H), 3.85 (dd, 1H, J = 4, 10Hz), 4.42 (s, 1H), 5.10 (d, 1H, J = 4Hz), 5.10 ( s, 2H), 5.10 (m, 1H) and 7.35 (m, 10H) ppm.

C. Benzyl 63 - C1 - (R) hydroxybenzyl penicillanate sulfone 1.35 g of n-chloroperbenzoic acid is added to a solution of 490 mg of benzyl-63 - (. 1- (R) -hydroxybenzylJ penicillanate in 50 ml of methylene chloride cooled to -5 ° C., and the resulting reaction mixture is kept under stirring for approximately 16 hours, the solvent is removed in vacuo and the residue is treated with an equal volume of ethyl acetate and The pH of the mixture is adjusted to 7.2 by adding a saturated solution of sodium bicarbonate and sufficient sodium bisulfite is added to decompose the excess of peracid (iodide and; negative starch). The organic phase is separated and washed successively with water at a pH of 8.2, with a "saturated solution" of sodium bicarbonate and with a solution of sodium chloride. the organic phase is separated, dried over magnesium sulfate and concentrated to 395 mg of a white solid. Matches the product on 100 g of silica gel using a mixture of toluene and ethyl acetate as the eluent at 10:12. Fractions 18 to 27 are combined and concentrated to obtain 148 mg of product in the form of an oil.

38

The NMR spectrum (CDCl 4) shows absorptions at 1.22 (s, 3H), 1.5 (s, 3H), 2.6 (m, 1H), 4.07 (dd, 1H, J = 10 , 5Hz), 4.47 (s, 1H), 4.67 (d, 1H, J = 5Hz), 5.2 (ABq, 2H), 5.63 (d, 1H, J = 10Hz) and 7, 37 (m, 10H) ppm.

5 C. 6 8 sulfone - (. 1- (S) -hydroxybenzyl benzyl penicillanate

The procedure of part C of Example 9 is repeated, starting with benzyl 6β- [1- (S) -hydroxybenzylJpenicillanate to obtain the desired product.

10 The NMR spectrum (CDCl 4) shows the absorptions at 1.19 (s, 3H), 1.5 (s, 3H), 2.8 (m, 1H), 4.20 (dd, 1H, J = 10.5Hz), 4.38 (d, 1H, J = 5Hz), 4.43 (s, 1H), 5.20 (ABq, 2H), 5.77 (d, 1H, J = 10Hz) and 7 , 37 (ra, 10H) ppm.

D. 68 - (. 1- (R) -hydroxybenzyl Jpenicillanic acid sulfone 140 mg of benzyl 6 - (. 1- (R) - hydroxybenzyl J penicillanate sulfone is added to a suspension of 148 mg palladium 5 % fixed on calcium carbonate in 20 ml of mixture of water and methanol at 1: 1 which has been prehydrogenated for 20 minutes under pressure of 332.5 kPa 20 and the hydrogenation is continued at an initial pressure of 329 kPa for another 40 minutes, another 140 mg of catalyst is added and the reduction is continued for 30 minutes, then a final weight of 140 mg of catalyst is added and the reduction is continued for a further 30 minutes, the spent catalyst is filtered and the The filtrate is extracted with ethyl acetate. The aqueous phase is separated, the pH is adjusted to 1.5 and fresh ethyl acetate is added. The extraction phase with ethyl acetate is rinsed with sodium chloride solution and dried over magnesium sulphate 30. Removal of the solvent under vacuum gives 90 m g of the product in the form of an oil.

* The NMR spectrum (CDC13) has absorptions at 1.50 (s, 3H), 1.67 (s, 3H), 4.1 (dd, 1H, J = 10.5Hz), 4.45 (s , 1H), 4.78 (d, 1H, J = 5Hz), 5.7 (d, 1H, J = 10Hz) 35 and 7.4 (m, 5H) ppm.

i 39 Of. 6ß- [1- (S) -hydroxybenzyljpenicillanic acid sulfone

170 mg of benzyl 6ß - (.l ~ (S) - hydroxybenzylpenicillanate sulfone) are added to a suspension of 170 mg of 5% palladium fixed on calcium carbonate and prereduced in 20 ml of mixture of water and methanol at 1: 1 and the hydrogenation is continued under pressure of 329 kPa for 40 minutes, a further 340 mg of catalyst are added and the reduction is continued for 3 hours, the catalyst is filtered, washed with a mixture of tetrahydrofuran 10 and water at 1: 1 and the combined filtrate and washing liquors are concentrated in. The residual water is extracted with ethyl acetate, then the aqueous phase is acidified to pH 1.5 and it is then extracted with ethyl acetate, the organic phase is rinsed with sodium chloride solution and dried over magnesium sulfate.

Removal of the solvent in vacuo gives 100 mg of the product melting at 164-165 ° C as it decomposes.

The NMR spectrum (CDClg) shows absorptions at 1.40 (s, 3H), 1.55 (s, 3H), 4.0 (dd, 1H, J = 5, 20 Hz),. 4.4 (d, 1H, J = 5Hz), 4.4 '(s, 1H), 5.7 (d, 1H, J = 10Hz) and 7.4 (m, 5H) ppm.

EXAMPLE 10

6ß- (.l- (S) -hydroxy-2-phenethyljpénicillanique acid sulfone and 6 0- (. 1- (R) -hydroxy-2-phenethyljpénicillanique A. 6a-bromo-6ß- [l- (R) -benzyl-hydroxy-2-phenethyljpenicillanate and 6 ^ ß-bromo-6a-il- (S) -benzyl-2-phenethylphenylpenicillanate 9.2 ml of a 2.5 M solution of benzyl is added. tert-butyl lithium to a solution of 9.0 g of 6,6-dibromo-benzyl penicillanate in 200 ml of toluene cooled to '-7S ° C and maintained under an argon atmosphere and the mixture is maintained resulting in stirring for 40 minutes, then 2.34 ml of phenylacetaldehyde are added, after stirring for 1 hour, 1.2 ml of acetic acid in 25 ml of diethyl ether are added and stirring is continued. -78 ° C. for 30 minutes The reaction mixture is allowed to warm to ambient temperature, then an equal volume of water is added, the organic phase is separated and kept, and the aqueous phase is extracted with ethyl acetate. The organic phase and organic extracts are combined, washed successively with water, a saturated solution of sodium bicarbonate and a solution of sodium chloride and dehydrated over magnesium sulfate. The oily residue weighing 11.0 g, which remains after the solvent has been removed under vacuum, is chromatographed on 500 g of silica gel, the eluent used being a mixture of chloroform and ethyl acetate at 20: 0.2.

The fractions 150 to 154 are pooled and concentrated to give 670 mg of benzyl 6 "-bromo-6 3 - (.l- (R) -hydroxy- 2-phenethyljpenicillanate.

The NMR spectrum (CDClg) shows an absorption at 1.35 (s, 1H), 1.53 (s, 1H), 2.85 (m, 3H), 4.23 (m, 1H), 4.41 15 (s, 1H), 5.13 (s, 2H), 5.57 (s, 1H) and 7.33 (m, 10H) ppm.

Fractions 155 to 195 are combined and concentrated to obtain 4.84 g of benzyl 63-bromo-6a- (, 1- (S) -hydroxy-2-phenethyljpenicillanate.

The NMR spectrum (CDCl3) shows an absorption 20 at 1.35 (s, 3H), 1.60 (s, 3H), 2.85 (m, 3H), 4.23 (m, 1H), 4, 41 (s, 1H), 5.08 (s,. 2H), 5.42 (s', 1H) and 7.33 (m, 10H) ppm.

B. 63 - (, 1- (R) -hydroxy-2-phenethylJpenicillanate and benzyl 63 - (. 1- (S) -hydroxy-2-phenethylJpenicillanate 25 A benzene solution (80 ml) containing 5.51 g benzyl 6a-bromo-6 3 - (. 1- (R) -hydroxy-2-phenethyl J penicillanate and benzyl 6 6-bromo-6a - (. l- (S) -hydroxy-2-phenethylJ-penicillanate , as isolated at A in Example 10, is treated with 3.2 ml of tri-n-butyltin hydride and the reaction mixture is heated at reflux under an atmosphere of nitrogen for 4 hours. is removed under reduced pressure and the residue is washed several times with hexane, the residue weighing 4.2 g is chromatographed on 500 g of silica gel, the eluent used being a 20: 3 mixture of chloroform and ethyl acetate.

Fractions 50 to 61 are combined and concentrated to obtain 596 mg of benzyl 6 3 - (, 1- (S) -hydroxy-2-phenethyljpenicillanate.

41

The NMR spectrum (CDCl 4) shows an absorption at 1.35 (s, 3H), 1.69 (s, 3H), 2.8 (m, 2H), 3.1 (m, 1H), 3, 55 (dd, 1H, J = 4, 10Hz), 4.23 (m, 1H), 4.40 (s, 1H), 5.15 (s, 1H), 5.35 (d, 1H, J = 4Hz), 7.22 (s, 5H) and 7.3 (s, 5H) ppm.

Fractions 65 to 75 are pooled and concentrated to give 1.5 g of benzyl 6β- [1- (R) -hydroxy-2-phenethyljpenicillanate.

The NMR spectrum (CDCl 4) shows an absorption at 1.35 (s, 3H), 1.6 (s, 3H), 2.78 (m, 2H), 2.9 (m, 1H), 3, 43 10 (dd, 1H, J = 5.9Hz), 4.30 (m, 1H), 4.40 (s, 1H), 5.12 (s, 1H), 5.22 (d, 1H, J = 5Hz), 7.19 (s, 5H) and 7.3 (s, 5H) ppm.

C. 68-ll- (S) -hydroxy-2-phenethyljpenicillanate sulfone

630 mg of m-chloroperbenzoic acid is added to a solution, cooled to 0-5 ° C, of 300 mg of benzyl 6ß - (.l- (S) -hydroxy-2-phenethylJ penicillanate in 50 ml of chloride methylene and the resulting reaction mixture is stirred for about 16 hours The solvent is removed in vacuo and the residue is treated with an equal volume of water and ethyl acetate The pH of the mixture is adjusted to 7 , 2 with a saturated solution of sodium bicarbonate and a sufficient quantity of sodium bisulfite is added to obtain a negative test with starch and iodide. The organic phase is separated, treated with an equal volume of water and The pH is adjusted to 8.2 as above. The organic phase is separated, washed with sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gives 320 mg of product in the form of an ^ oil.

s 30 The NMR spectrum (CDClg) shows an absorption at 1.22 (s, 1H), 1.5 (s, 1H), 2.8 (m, 2H), 3.8 (dd, 1H, J = 5,: 10Hz), 4.42 (s, 1H), 4.6 (d, 1H, J = 5Hz), 4.75 (m, 1H), 5.18 (ABq, 2H), 7.2 ( s, 5H) and 7.3 (s, 5H) ppm.

C. Benzyl 6ß- [1- (R) -hydroxy-2-phenethyljpenicillanate sulfone 35

Following the procedure of paragraph C of Example 10 and starting from 700 mg of benzyl 6ß- [1- (R) -hydroxy-2-phenethylJ-penicillanate and 850 mg of m-chloroperbenzoic acid, 610 is obtained. mg of the desired product in the form of an oil.

42

The NMR spectrum (CDCl 4) shows an absorption at 1.25 (s, 1H), 1.52 (s, 1H), 2.8 (m, 2H), 3.7 (dd, 1H, J = 5 , 10Hz), 4.42 (s, 1H), 4.55 (d, 1H, J = 5Hz, 4.80 (m, 1H), 5.18 (ABq, 2H), 7.22 (s, 5H ) and 7.3 (s, 5H) ppm.

5 D. Sodium salt of acid sulfone 68- [1- (R) -hydroxy-2-phenethylJpénicillanigüë

600 mg of benzyl 6ß— (. 1— (R) - hydroxy-2-phenethylJ penicillanate sulfone is added to a suspension of 600 mg of 5% palladium on calcium carbonate, prehydrogenated for 20 minutes at 329 pressure kPa in 20 ml of mixture of water and methanol at 1: 1. After continuing the hydrogenation for 35 minutes under pressure of 336 kPa, another 600 mg of catalyst is added and the hydrogenation is continued under pressure of 15,336 kPa for 10 minutes The spent catalyst is filtered and washed with a mixture of water and methanol at 1: 1. The filtrate and the washing liquors are combined and the methanol is removed under reduced pressure. aqueous (pH 8.0) with ethyl acetate and the phases are separated. The aqueous phase is acidified to a pH of 1.8 and extracted with ethyl acetate. is separated, rinsed with sodium chloride solution and dehydrated over magnesium sulfate. Removal of the solvent under vacuum gives 390 m g of product as a white solid.

The free acid is dissolved in ethyl acetate containing a small amount of diethyl ether. To this solution is added 177 mg of sodium 2-ethylhexanoate and the solution is stirred for 1 hour. The sodium salt precipitate of the product is filtered and dried; 250 mg of substance melting at 205 ° -208 ° C. are obtained while decomposing.

The NMR spectrum (D2O) shows an absorption at 1.42 (s, 3H), 1.65 (s, 3H), 2.9 (m, 2H), 4.0 (dd, 1H, J = 5, 35 10Hz), 4.3 (s, 1H), 4.9 (m, 1H), 5.0 (d, 1H, J = 5Hz) and 7.3 (s, 5H) ppm.

43 Of. 6ß- [1- (S) -hydroxy-2-phenethylJ penicillanic acid sulfone

320 mg of benzyl acid sulfone 60 - (. 1- (S) -hydroxy-2-phenethylJ penicillanate) to a suspension of 320 mg of 5% palladium on prereduced calcium carbonate in 20 ml of mixture of water and methanol 1: 1, and the resulting mixture was shaken in an atmosphere of hydrogen at an initial pressure of 329 kPa for 30 minutes, the catalyst was filtered, washed with a mixture of water and of methanol and the washing liquors and the filtrate are combined The aqueous residue remaining after the methanol has been removed in vacuo is extracted with ethyl acetate and it is then extracted with fresh ethyl acetate. The extract is rinsed with a sodium chloride solution, dried over magnesium sulfate and evaporated to give 80 mg of an oil which solidifies and melts at 80-85 ° C as it decomposes.

The NMR spectrum (CDCl 4) shows an absorption at 1.42 (s, 1H), 1.65 (s, 1H), 2.9 (m, 2H), 4.0 (dd, 1H, J = 5 , 20 10Hz), 4.3 (s, 1H), 4.8 (m, 1H), 4.85 (d, 1H, J = 5Hz) and 7.3 (s, 5H) ppm.

EXAMPLE 11

6ß - (.l- (R) -hydroxy-3-phenylpropylJpenicillanic acid sulfone and 25 6ß - (, l- (S) -hydroxy-3-phenylpropyljpenicillanic acid A. 6a-bromo-6ß- [l - (R) and (S) -hydroxy-3-phenylpropylj-benzyl penicillanates

4.5 g of benzyl 6,6-dibromopenicillanate are dissolved in 100 ml of anhydrous toluene and the resulting solution is cooled to -70 ° C. 7.3 ml of tert-butyl lithium are added to the cooled solution. After stirring in the refrigerator for 20 minutes, 1.3 ml of hydrocinnamaldehyde are added and stirring is continued for 20 minutes, 0.57 ml of acetic acid is added and the reaction mixture is allowed to warm to room temperature . The toluene is removed in vacuo and an equal volume of chloroform and water is added. The organic phase is separated, rinsed with sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gives 5.3 g of the product in the form of an oil. The product is purified by chromatography on silica gel, the eluent used being a mixture of chloroform and ethyl acetate at 20: 1.

The fractions 88 to 155 are combined and the solvent is removed in vacuo to obtain 3.2 g of the product.

Analysis: C% H% N%

Calculated for C24H20 ° 4NSBr: 57.2 5.2 2.8

Found: 56.5 5.2 2.9 B. 6 3 - (, 1- (R) -hydroxy-3-phenylpropyl jpenicillanate 10 and χυ 613- (1- (S) -hydroxy-3-phenylpropylJ penicillanate benzyl

It is refluxed under a nitrogen atmosphere. for 2 hours and 40 minutes a solution of 1.5 g of 6 and bromo-6 3- (1- (R) and (S) -hydroxy-3-phenylpropylJ benzicillicpenicillanate and 1.72 ml of trihydride -n-butyl-tin in 100 ml of benzene The solvent is removed in vacuo and the residue is chromatographed (3.7 g) on 150 g of silica gel using a mixture of chloroform and acetate as eluent ethyl at 20: 1.

Fractions 63 to 80 are pooled and the solvent is removed to give 244 mg of benzyl 6β- (1- (S) -hydroxy-3-phenylpropylPenicillanate as an oil.

The NMR spectrum (CDCl3) shows an absorption 25 to 1.40 (s, 3H), 1.50 (s, 3H), 1.8 (m, 2H), 2.8 (m, 3H), 3, 59 (dd, 1H, J = 4, 10Hz), 4.1 (m, 1H), 4.43 (s, 1H), 5.20 (s, 2H), 5.43 (d, 1H, J = 4Hz), 7.25 (s, 5H) and 7.4 (s, 5H) ppm.

The fractions 114 to 133 are combined and the solvent is evaporated to obtain 369 mg of benzyl 3- (1- (R) -hydroxy-30-3-phenylpropylJpenicillanate) in the form of an oil.

c, The NMR spectrum (CDC13) has an absorption at 1.38 (s, 3H), 1.60 (s, 3H), 1.8 (m, 2H), 2.8 (m, 3H), 3 , 55 (dd, 1H, J = 4.9Hz), 4.1 (m, 1H), 4.43 (s, 1H), 5.20 (s, 2H), 5.35 (d, 35 1H, J = 4Hz), 7.25 (s, 5H) and 7.4 (s, 5H) ppm.

45 C. Sulfone of 6ß - (, l- (R) -hydroxy-3-phenylpropylJ Benzyl penicillanate

700 mg of m-chloroperbenzoic acid are added to a solution of 585 mg of benzyl 68 - (. 1- (R) -hydroxy-3-phenylpropylJ-5 penicillanate in 35 ml of methylene chloride cooled to 0-5 ° C and the reaction mixture is stirred for about 16 hours, the solvent is removed under reduced pressure and the residue is treated with an equal volume of water and ethyl acetate, the pH is adjusted to 7.2 with 10 a saturated solution of sodium bicarbonate and the organic phase is separated, an equal volume of water is added to the ethyl acetate phase and the pH is adjusted again as above to 8.4. the ethyl acetate phase, it is washed with a saturated sodium bicarbonate solution (3 times 50 ml) and with a sodium chloride solution, then it is dried over magnesium sulfate. solvent gives 678 mg of the product in the form of an oil which crystallizes on standing and melts at 142-143 ° C.

The NMR spectrum (CDCl 4) shows absorption at 1.30 (s, 3H), 1.6 (s, 3H), 1.8. (m, 2H), 2.8 (m, 2H), 3.83 (dd, 1H, J = 5.9Hz), 4.50 (s, 1H), 4.55 (d, 1H, J = 5Hz ), 4.75 (m, 1H), 5.2 (ABq, 2H), 7.2 (s, 5H) and 7.38 (s, 5H) ppra.

C »Sulfone of 6 8 - (, 1- (S) -hydroxy-3-phenylpropyl J-25 benzyl penicillanate

The procedure of paragraph C of Example 11 is followed, starting with 300 mg of benzyl 6 8 - (. 1- (S) -hydroxy-3-phenylpropyljpenicillanate and 361 mg of m-chloroperbenzoxque acid in 35 ml methylene chloride to obtain 346 mg of product as an oil.

The NMR spectrum (CDClg) shows absorption; „At 1.28 (s, 3H), 1.52 (s, 1H), 1.8 (m, 2H), 2.80 (m, 2H), 3.9 (dd, 1H, J = 5, 10Hz), 4.45 (s, 1H), 4.62 (m, 1H), 4.67 (d, 1H, J = 5Hz), 5.22 (ABq, 2H), 7.22 (s, 5H ) and 7.38 (s, 5H) ppm.

35 46 D. 68- [1- (R) -hydroxy-3-phenylpropylJ-penicillanic acid sulfone

678 mg of 6 6- (1- (R) -hydroxy-3-phenylpropylJ benzicillanate) sulfone is added to a suspension of 700 mg of 5% palladium fixed on prehydrogenated calcium carbonate in 20 ml of mixture of Water and methanol 1: 1. The mixture is shaken by shaking in a hydrogen atmosphere and at an initial pressure of 364 kPa for 1 hour, at this point 700 mg of catalyst are added further and the mixture is continued. hydrogenation for 1 hour, the catalyst is filtered and washed with a mixture of water and methanol, the washers are combined with the filtrate and the methanol is removed in vacuo, the aqueous residue is extracted with acetate ethyl, then adjust the pH of the aqueous phase to 1.5 and extract with fresh ethyl acetate, rinse the organic phase with sodium chloride solution and wash it dehydrates over magnesium sulphate Removal of the solvent gives 304 mg of product melting at 138-140 ° C. as it decomposes.

The free acid sample (190 mg) is dissolved in ethyl acetate and the solution is then treated with 99 mg of sodium 2-ethylhexanoate. After stirring for about 16 hours, the sodium salt of the desired product is filtered and dried; 165 mg are obtained.

The NMR spectrum (DMSO-dg) of the free acid shows absorption at 1.45 (s, 1H), 1.53 (s, 1H), 1.8 (m, 2H), 2.80 ( m, 2H), 3.85 (dd, 1H, J = 5.9Hz), 4.35 (s, 1H), 4.60 (d, 1H, J = 5Hz), 4.75 (m, 1H) and 7.23 (s, 5H) ppm.

Of. Acid sulfone 6 8 - (. 1- (S) -hydroxy-3-phenylpropyl j-30 penicillanic

The procedure of paragraph D of i is repeated. Example 11, starting from 346 mg of 68 - (. 1- (S) - hydroxy-3-phenylpropyljpenicillanate sulfone and 350 mg of 5% palladium fixed on calcium carbonate in 20 ml of mixture of water and methanol at 1: 1 to obtain 196 mg of the desired product, melting at 146-148 ° C while decomposing.

A 126 mg sample of 6ß- (1- (S) -hydroxy-3-hydroxy-3-phenylpropylJpenicillanic acid sulfone is dissolved in a small amount of ethyl acetate and the solution is then treated with 57 mg of 2-ethylhexanoate Add a little diethyl ether and filter the resulting precipitate, then dry to obtain 57 mg of the sodium salt of the desired product.

5 The nuclear magnetic resonance spectrum (DMSO-dg) of the free acid shows an absorption at 1.47 (s, 1H), 1.60 (s, 1H), 2.0 (m, 2H), 2, 8 (m, 2H), 3.9 (dd, 1H, J = 5.10Hz), 4.40 (s, 1H), 4.67 (m, 1H), 4.70 (d, 1H) and 7 , 2 (s, 5H) ppm.

10 EXAMPLE 12

Acid sulfone 68 - (. L- (R) -hydroxy-l- (2'-pyEidvl) methyl) “penicillanic and

Acid sulfone 6g- [l- (S) -hydroxy-l- (21-pyridyl) methyl] l-15 penicillanic A. 6ß— j, 1— (R) and (S) -hydroxy-1- (2 '-pyridyl) methyl) -benzyl penicillanates

11.8 ml of tert-butyl lithium are added to a solution - cooled to -78 ° C of 9.0 g of benzyl 6,6-dibromo-penicillanate in 200 ml of toluene under an atmosphere of argon and the resulting green solution is kept under stirring. for 30 minutes "1.9 ml of 2-pyridylcarboxaldehyde are added and the reaction mixture is stirred in the refrigerator for 45 minutes. Then 1.2 ml of acetic acid in 25 ml of diethyl ether is added over a period of 20 minutes. The mixture is kept stirred in the refrigerator for 30 minutes, then allowed to warm to 10 ° C. The reaction mixture is chromatographed on a "Florisil" column using a 2: 1 mixture of toluene and ethyl acetate as eluent. Fractions 3 to 5 (300 ml each) are combined and evaporated to give 4.8 g of an oil.

The oil is dissolved in 60 ml of anhydrous benzene supplemented with 3.2 ml of tri-n-butyltin hydride. The resulting reaction mixture is then heated to reflux under a nitrogen atmosphere for 2.5 hours. A further 2.0 ml of hydride is added and heating is continued for approximately 16 hours. The benzene is removed in vacuo and the residue is suspended several times in hexane. The remaining oil is chromatographed on 500 g of “” gel. 48 φ silica using a 2: 1 mixture of toluene and ethyl acetate as eluent.

Fractions 104 to 131 are combined and the solvent is removed under reduced pressure to obtain 480 mg of 6 6-5 (.1- (R) -hydroxy-1- (2 '-pyridyl) methyl] benzyl penicillanate in the form of an oil.

The NMR spectrum (CDCl 4) shows an absorption at 1.45 (s, 3H), 1.73 (s, 3H), 3.87 (dd, 1H, J = 4, 10 Hz), 4.53 (s , 1H), 4.65 (m, 1H), 5.20 (m, 1H), 5.23 (s, 2H), 5.48 (d, 10 1H, J = 4Hz), 7.4 (s , 5H), 7.5 (m, 3H) and 8.6 (m, 1H) ppm.

Fractions 136 to 190 are combined and the solvent is removed in vacuo to obtain 950 mg of benzyl 66 - (.l- (S) -hydroxy-l- (2'-pyridyl) methylJ penicillanate as an oil.

The NMR spectrum (CDCl 4) shows an absorption at 1.40 (s, 3H), 1.68 (s, 3H), 4.0 (m, 1H), 4.05 (dd, 1H, J = 4.9Hz), 4.55 (s, 1H), 5.2 (s, 2H), 5.22 (m, 1H), 5.46 (d, 1H), J = 4Hz), 7.3 ( s, 5H), 7.4 (m, 3H) and 8.5 (m, 1H) ppm.

B. 6 6 - (, 1- (R) -hydroxy-1- (2'-pyridyDmethyl ·) -2o benzyl penicillanate sulfone

Operating under a nitrogen atmosphere, 500 mg of m-chloroperbenzoic acid are added to a 480 mg solution of 66 - (. 1- (R) -hydroxy-1- (2 'pyridyl) methyl benzylpenicillanate in 40 ml of methylene chloride cooled to 0-25 ° C. After stirring for 1 hour, the solvent is removed in vacuo and the residue is treated with an equal volume of water and ethyl acetate. pH 7.2 by addition of saturated sodium bicarbonate solution, then add sufficient sodium bisulfite until a negative starch and iodide test is obtained. the aqueous phase was separated and fresh ethyl acetate was added, the pH was raised to 8.2 as above, the ethyl acetate phase was separated, rinsed with a solution of sodium bicarbonate and saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gives 480 mg of an oil which is then chromatographed. ur 50 g of silica gel using ethyl acetate as eluent. Fractions 22 to 55 are combined and the solvent is removed in vacuo to obtain 125 mg of product.

'- ~ 49 r

The NMR spectrum (CDCl3) shows an absorption at 1.22 (s, 3H), 1.50 (s, 3H), 4.40 (s, 1H), 4.79 (m, 1H), 4.80 (d, 1H, J = 4Hz), 5.18 (ABq, 2H, J = 12Hz), 5.6 (m, 1H), 7.2 (m, 3H), 7.25 (s, 5H) and 8.1 (m, 1H) ppm.

5 B '. Sulfone of 68- [l- (S) -hydroxy-l- (2'-pyridyl) methÿl) benzyl penicillanate

Starting from 250 mg of 68 - (. 1- (S) -hydroxy-1- (2'-pyridyl) methylJ benzyl penicillanate and 320 mg of m-chloroperbenzoic acid in 25 ml of methylene chloride and · = 10 following the procedure of paragraph B of Example 12, 240 mg of the desired product are obtained in the form of a white solid substance melting at 140-145 ° C.

The NMR spectrum (CDClg) shows an absorption at 1.23 (s, 3H), 1.59 (s, 3H>, 4.6 (S, 1H), 4.8 (m, 2H), 5.3 15 (ABq, 2H, J = 12Hz), 5.95 (m, 1H), 7.4 (s, 5H), 7.5 (m, 3H) and 8.4 (m, 1H) ppm.

C. Acid sulfone 6 8- (. 1- (R) -hydroxy-1- (2'-pyridyl) methyl) -penicillanic

120 mg of sulfone of 6 8 - (. 1- (R) -20 hydroxy-1- (2'-pyridyl) methylJ benzicillanate is added to a suspension of 120 mg of 5% palladium on calcium carbonate reduced, in 20 ml of methanol and water mixture at 1: 1 and the mixture is shaken in an atmosphere of hydrogen at an initial pressure of 25 329 kPa for 30 minutes. A further 120 mg of catalyst are added and the hydrogenation is continued for 45 minutes at a pressure of 329 kPa. The catalyst is filtered, washed with a mixture of methanol and water and the washing liquors and the filtrate are combined. The methanol is removed in vacuo and it is extracted to the aqueous residue with ethyl acetate * The aqueous phase is lyophilized to obtain 90 mg of the desired product in the form of the calcium salt.

The NMR spectrum (D2O) of the calcium salt shows absorption at 1.50 (s, 3H), 1.65 (s, 3H), 4.35 35 (s, 1H), 4.70 (m, 1H ), 5.18 (d, 1H, J = 4Hz), 5.65 (d, 1H, J = llHz), 7.7 (m, 3H) and 8.6 (wide d, 1H, J = 5Hzj ppm .

* ". 50 C. Acid sulfone 68- (. L- (S) -hydroxy-l- (2'-pyridyl) methyl) -penicillanic

The procedure of part C of Example 12 is repeated, starting from 240 mg of 6 3 - (. 1- (S) -hydroxy-1-5 (2'-pyridyl) methyl] benzyl penicillanate and 480 mg of palladium fixed on calcium carbonate in 20 ml of mixture of methanol and water and thus 170 mg of the calcium salt of the desired product are obtained.

EXAMPLE 13 Starting from benzyl 6,6-dibromopenicillanate and suitably chosen pyridylcarboxaldehyde and using the procedure of Example 12, the following compounds are prepared: acid sulfone 6 8 - (. 1- (R) -hydroxy-1- (3'-pyridyljmethyl J-15 penicillanic; acid sulfone 63 - (. 1- (R) -hydroxy-1- (4'-pyridyljmethylJ-penicillanic; sulfone acid 68 - (. 1 - (S) -hydroxy-1- (4'-pyridyl) methylj-penicillanic; and acid sulfone 68 - (. 1- (S) -hydroxy-1- (3'-pyridyljmethylJ-penicillanic.

EXAMPLE 14

6 β-acetoxymethylpenicillanic acid sulfone A. Benzyl 68-acetoxymethylpenicillanate sulfone 25 0.1 ml of acetyl chloride and 10 mg of 4-dimethylaminopyridine are added to a solution of 500 mg of benzyl 68-hydroxymethylpenicillanate sulfone and 0.196 ml of triethylamine in 20 ml of methylene chloride cooled to 0-5 ° C. After stirring for 20 minutes, the solvent is removed in vacuo and ethyl acetate is added to the residue. The resulting solid is separated and the filtrate is washed successively with water, water at pH 1.0, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuo to give 600 mg of product as an oil.

The NMR spectrum (CDCl 4) shows an absorption at 1.30 (s, 3H), 1.59 (s, 3H), 2.1 (s, 3H), 4.2 (m, 1H), 4, 5 • '51 4 (s, 1H), 4.6 (m, 2H), 4.65 (â, 1H, J = 4Hz), 5.22 (ABq, 2H, J = 12Hz) and 7.4 ( s, 5H) ppm.

B. 68-Acetoxymethylpenicillanic acid sulfone

600 rag of benzyl-63-5 acetoxymethylpenicillanic acid sulfone are added to a suspension of 600 mg of 5% palladium on calcium carbonate, previously reduced in 20 ml of water with hydrogen under pressure of 350 kPa for 20 minutes. The resulting mixture was shaken in a hydrogen atmosphere at an initial pressure of 350 kPa for 45 minutes. The catalyst is filtered and washed with a mixture of methanol and water. The filtrate and the washing liquors are combined and lyophilized to obtain 360 mg of the desired product in the form of the calcium salt.

The NMR spectrum (1 ^ O) to the calcium salt shows absorption at 1.5 (s, 3H), 1.61 (s, 3H), 2.18 (s, 3H), 4.25 (s , 1H), 4.3 (m ', 1H), 4.60 (m, 2H) and 5.07 (d, 1H, J = 4Hz) ppm.

EXAMPLE 15 Acid sulfone 6g-stearoyloxymethypenicillanicrue A. Sulfone of benzyl 63-stearoyloxymethylpenicillanate

Starting from 500 mg of benzyl 6 6-hydroxy-methylpenicillanate, 430 mg of stearoyl chloride, 0.196 ml of triethylamine and 10 mg of 4-dimethyl-25-aminopyridine and following the procedure of paragraph A of Example 14, 784 mg of the desired product is obtained in the form of an oil.

The NMR spectrum (CDCl3) shows absorption at 1.4 (m, 3H), 2.4 (m, 2H), 4.2 (m, 1H), 4.52 (s, 1H), 4.60 • 30 (m, 2H), 4.63 (d, 1H, J = 4Hz), 5.22 (ABq, 2H, J = 12Hz) and 7.4 (s, 5H) ppm.

B. 6B-stearoyloxymethylpenicillanic acid sulfone

Following the procedure in paragraph B of Example 14 and starting from 776 mg of 6ß-35 sulfone benzyl stearoyloxymethylpenicillanate and 880 mg of 5% palladium fixed on calcium carbonate in 25 ml of methanol mixture and water at 1: 1, 524 mg of the calcium salt of the desired product are obtained. The calcium salt is then suspended in 200 ml of ethyl acetate and 200 ml of water and the suspension is treated with a sufficient quantity of 6N hydrochloric acid so that the pH is equal to 2, 0. The ethyl acetate phase is separated, rinsed with saturated sodium chloride solution and dried over magnesium sulfate. By removing the solvent, 260 mg of the desired product is obtained in the form of a white solid.

The NMR spectrum (CDCl 4 and DMSO-dg) shows absorption at 1.4 (m, 3H), 2.35 (m, 2H), 4.2 (m, 1H), 4.39 (s, 1H), 4.60 (m, 2H) and 4.63 (d, 1H, J = 4Hz) ppm.

EXAMPLE 16

Starting from the suitably chosen acid chloride and the desired benzyl 63-hydroxyalkylpenicillanate sulfone and following the procedures of paragraphs A and B of Example 14, the following compounds are prepared: acid sulfone 63- [1- (R) acetoxy-n-butylJ penicillanic; 63-il- (S) acetoxy-3-methyl-n-butylJ-20 penicillanic acid sulfone; acid sulfone 6 3 - (. 1- (S) acetoxy-2-phenethyl Jpenicillanic acid sulfone 6 3-il- (S) acet-oxy-1- (3'-pyridyl) methyl J ~ penicillanic; 6 3-n-butycvioxymethylpenic: .llanic acid sulfone; 25 63-il- (S) -s-butyryloxy-n-propylJ-penicillanic acid sulfone; 63 - (. 1- (S) acid sulfone -n-butyryloxy-2-methyl-n-propylJ-penicillanic; acid sulfone 63-il- (S) -n-butyryloxybenzylJ-30 penicillanic; i sulfone acid 6 3 - (, 1- (R) - n-butyryloxy-1- (2 '-pyridyl) -. methylJ penicillanic acid 63-il- (S) -s-butyryloxy-1- (4'-pyridyl) -methylJ penicillanic acid 35 -n-valeryloxymethylpenicillanic; acid sulfone 63 - (. 1- (S) -n-valeryloxyethylJpenicillanic; acid sulfone 63-il- (R) -isovaleryloxy-n-pentylJ-penicillanic; 53 Λ acid sulfone 63 - (1- (R) -trimethylacetoxy-2,2-dimethyl-n-propylJ penicillanic; 6ß acid sulfone - (. l- (R) -n-valeryloxy-3-phenylpropyl J-penicillanic; 5 acid sulfone 63- [1- (R) -isovaleryloxy-1- (2'-pyridyl) -methylJpé Nicillanic; 6 3 - (. 1- (S) -trimethylacetoxy-1- (4 '-pyridyl) -methylJpenicillanic acid sulfone; 63-octanoyloxymethylpenicillanic acid sulfone; 10 63- (l- (R) - acid sulfone octanoyloxy-n-pentylJ-penicillanic acid sulfone 6 3 - (. 1- (S) -octanoyloxy-2-phenethylJ-penicillanic acid sulfone 63- (1- (S) -octanoyloxy-1- (3 '-pyridyl) -15 methylJ penicillanic; 63-hendecanoyloxymethylpenicillanic acid sulfone; 63- (l- (S) hendecanoyloxy-2-methyl-n-propylJpenicillanic acid sulfone; 6ß- (l- (R) acid sulfone hendecanoyloxybenzylJ-20 penicillanic acid sulfone 63 - (. 1- (S) hendecanoyloxy-1- (4'-pyridyl) -methylJpenicillanic acid sulfone 63-palmitoyloxymethylpenicillanic acid sulfone 6ß- (l- (S ) -palmitoyloxyethylJ penicillanic; 25 acid sulfone 6 3 - (. 1- (R) -palmitoyloxy-2-phenethyl J-penicillanic acid sulfone 6 3 - (. 1- (S) -palmitoyloxy-1- (3 '-pyridyl) -methylJ penicillanic acid sulfone 63- [l- (S) -palmitoyloxy-l- (4'-pyridyl) -30 methylJ penicillanic acid; sulfone 6 3 - (. 1- (R) -stearoyloxyethyl Jpenicillanic acid; . . 63- (1- (S) -stearoyloxy-2,2-dimethyl-n-propylJpenicillanic acid sulfone? 63-il- (R) -stearoyloxy) -3-phenylpropylJ-35 penicillanic sulfone; 6ß- (l- (S) -stearoylo ^ y-1- (2'-pyridyl) -methylJpenicillanic acid sulfone; and - 54 6B acid sulfone - (. l- (S) -stearoyl-l- ( 4 * -pyridyl) -methyl) penicillanic.

EXAMPLE 17

Sulfone of 6β-benzoyloxymethylpenicillanic acid 5 A. Sulfone of benzyl-benzoyloxymethylpenicillanic acid

0.094 ml of benzoyl chloride and 10 mg of 4-dimethylaminopyridine are added to a solution of 300 mg of benzyl 68-hydroxymethylpenicillanate sulfone and 0.11 ml of triethylamine in 25 ml of methylene chloride cooled to 0-5 ° C. After stirring in the refrigerator for 30 minutes, the solution is washed successively with water, water at a pH of 1.0, a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The residue is chromatographed on 20 g of silica gel using an 8: 1 mixture of toluene and ethyl acetate as eluent. Fractions 15 to 30 are combined and concentrated in vacuo to obtain 280 mg of the product in the form of an oil.

The NMR spectrum (CDCl 4) exhibits absorption at 1.26 (s, 3H), 1.53 (s, 3H), 4.2 (m, 1H), 4.57 (s, 1H), 4.79 (d, 1H, J = 4Hz), 4.9 (m, 2H), 5.2 (ABq, 2H, J = 12Hz), 7.4 (s, 5H), 7.5 (m, 3H) and 8.2 (m, 2H) ppm.

B. 63-Benzoyloxymethylpenicillanic acid sulfone 270 mg of benzyl-68-benzoyloxymethylpenicillanic acid sulfone is added to a suspension of 270 mg of 5% palladium on preduced calcium carbonate in 15 ml of water mixture and methanol 1: 1, and the resulting mixture was shaken in a hydrogen atmosphere at an initial pressure of 350 kPa for 40 minutes. The catalyst is filtered and the methanol is evaporated., The aqueous residue is extracted with ethyl acetate, then lyophilized giving the calcium salt of the product (200 mg).

35 The nuclear magnetic resonance spectrum (D20) of calcium salts shows absorption at 1.5 (s, 3H), 1.6 (s, 3H), 4.8 (m, 3H), 5.1 (d , 1H, J = 4Hz), 7.6 (m, 3H) and 8.0 (m, 2H) ppm.

- '55 EXAMPLE 18

Starting from the suitably selected benzyl 6β-hydroxyalkyl penicillanate sulfone and the desired benzoyl chloride and using the procedures of paragraphs A and B of Example 17, the following esters are prepared: GH '° \ f ° 2, - == 3 T / CHtzilf'CH3

R4 ° '"-C02H

X R. * - —4— ~ 4-Cl-- H- 2-F-, - H- 4-CH3- H- 4-C1-. CH3 ~ (S) 4 “Cl- CH3- (R) 4-CF3- CH3t (R) 4-F- -CH3 (CH2) 2- (R) 2- CH3- CH3 (CH2) 2- (R) 3 - CH30- CH3 (CH2) 2- (R) 2- F- CH3CH (CH3) CH2- (S) H- CH3 (CH2) 2- (R) * H- (CH3) 3C- (S) 3- C1 -. (CH3) 3C- (R) / 56 x R, H 'C6H5-' (S) 5 3-CH3- C6H5- (3) 4-CH3O- c6H5- (R) 2-1 · - C6H5CH2- (S) 2-CH3- C6H5 (CH2) 2- (r, “-R- c6H5 (CH2) 2- (R) 10 4 ~ CIy- C6H5 (CH2> 2- (S) 4-œ3-. C6h5 (ch2) 2 - (s) H- 2'-05H4H- (R) 3 ~ CH3 ”2'-C3H4H- (S) 4-CP3- 2'-C5H4N- (r) 15 H '3'-C5H4N- (S) 4 -CH3O- 3'-CsH4N- (S) 4-CHj- 3'-C5H4N- (S) 3- p- 3'-C5H4N- (r) H- 4'-C5H4N- (R) 20 '2-p - · - 4'-C5H4N- (R) 4_CF3- · 4'-C5H4N- - (S) 4- CH3- 4> -C5H4N- (S) EXAMPLE 19 25 Acid sulfone 6 ß-41-aminobenzoyloxymethylpenicillanic A. Sulfone Benzyl 6g-4l-nitrobenzoyloxymethylpenicillanate

Operating under an argon atmosphere, 264 mg of 4 '-nitrobenzoyl chloride and 10 mg of 4-30 dimethylaminopyridine are added to 500 mg of benzyl 6ß-hydroxy-methylpenicillanate sulfone and 0.196 ml of triethylamine in 20 ml. methylene chloride cooled to 0-5 ° C = After stirring in the refrigerator for 30 minutes, the reaction mixture is washed successively with water, water at pH 1.0, saturated bicarbonate solution sodium and a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuo to give 657 mg of the product as a semi-solid substance.

. * 57

The NMR spectrum (CDClg) shows an absorption at 1.33 (s, 3H), 1.58 (s, 3H), 4.3 (m, 1H), 4.58 (s, 1H), 4.8 (d, 1H, J = 4Hz), 4.9 (m, 2H), 5.23 (ABq, 2H, J = 12Hz), 7.39 (s, 5H) and 8.2 (s, 4H) ppm .

5 B. 6ß-41-aminobenzoyloxymethylpenicillanic acid sulfone

650 mg of benzyl-68-4 'sulfone - nitrobenzoyloxymethylpenicillanic acid is added to a suspension of 650 mg of 5% palladium on prereduced calcium carbonate in 20 ml of a mixture of water and methanol at 1: 1 and 10 10 ml of tetrahydrofuran, and the resulting mixture is shaken by shaking in an atmosphere of hydrogen at an initial pressure of 350 kPa for 1 hour. The spent catalyst is filtered and the residue is partitioned between ethyl acetate and water. The aqueous phase is separated and lyophilized to give 560 mg of the product as the calcium salt.

The NMR spectrum (D20) of the calcium salt shows an absorption at 1.5 (sf 3H), 1.6 (s, 3H), 4.39 (s, 1H), 4.70 (m, 3H), 5.1 (d, 1H, J = 4Hz), 6.78 (df 2H, J = 9Hz) and 7.8 (d, 2H, J = 9Hz) ppm.

20 EXAMPLE 20

The procedure of Example 19 is repeated, starting from the corresponding benzyl 66-hydroxyalkylpenicillanate sulfone and nitrobenzyl chloride suitably chosen to obtain the following compounds in the form of their calcium salts.

* 58 Η ο ο = 2 Ο CH3 <λ -.- NH2

Position of NÏÏp; on the nucleus

3- H

2- H

2— CH3- (R) 4-. CH3- (R) 4- CH3- (S) 2- CH3 (CH2) 2- (R) 3- CH3 (CH2) 2- (R) 3- CH3CH (CH3) CH2-_ '(S) 4- · .'... CH3C-H (CH3) CH2- (S) 2 “.. (CH3) 3C- (R) 3- (CH3) 3C- (S) 3- CgH5- (R) 4" C6H5 "( R) 2- · C6H5CH2- (S) 3- C6H5CH2- (S) 4- CgH5CH2- (S) 2 ~ CgH5 (CH2) 2- (R) 4- (R) 2- 2-C5H4N- '(R) 4- 2-C-H4N- (R) 3- 3-C5H4N- (S) 3- '4-C5H4N- (S) 4- 4-C5H4N- (R) “59 EXAMPLE 21

Benzyl 6ß-41-tolylsulfonyloxymethylpenicillanic acid sulfone A. 63-4'-tolylsulfonyloxymethylpenicillanate

800 mg of benzyl 63-hydroxy-5-methylpenicillanate in 1.5 ml of pyridine are added dropwise to 1.24 g of 4-tolylsulfonyl chloride in 3.5 ml of pyridine cooled to 0 ° C. and under an atmosphere argon. After stirring in the refrigerator for 2 hours, 0.80 ml of water is added and stirring is continued for 30 minutes at 10 0 ° C. The reaction mixture is added to 30 ml of water and the pH is adjusted to 1.0 by addition of dilute hydrochloric acid. The aqueous phase is extracted with diethyl ether and the organic phase is separated, then washed successively with 1.2 N hydrochloric acid, water and a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and evaporated to obtain 841 mg of an oil which is chromatographed on 100 g of silica gel using a mixture of chloroform and ethyl acetate as eluent. 10: 1. The 20 fractions 10 to 25 are combined and the solvent is removed in vacuo to obtain 680 mg of the product.

B. 63-4'-tolylsulfonyloxymethylpenicillanic acid

680 mg of benzyl 63-4'-tolylsulfonyloxy-methylpenicillanate is added to a suspension of 680 mg of 5% palladium on prereduced calcium carbonate in 20 ml of 1: 1 mixture of methanol and water and continues the pressure reduction of 343 kPa for 30 minutes. A further 680 mg of catalyst is added and the reaction is continued for a further 30 minutes. The catalyst is filtered and the methanol is removed from the filtrate by evaporation. The aqueous residue is extracted with ethyl acetate and the aqueous phase is acidified to a pH of 2.0. Fresh ethyl acetate is used to extract the acidified aqueous phase. The organic phase is separated, dried over magnesium sulfate and the solvent is removed in vacuo to give 463 mg of the product as a semi-solid substance.

60

The NMR spectrum (CDCl 4) shows an absorption at 1.57 (s, 3H), 1.6 (s, 3H), 2.37 (s, 3H), 4.1 (m, 3H), 4, 2 (s, 1H), 5.4 (d, 1H, J = 4Hz) and 7.6 (ABq, 4H, J = 10Hz) ppm.

C. 3-4'-tolylsulfonyloxymethylpenicillanic acid sulfone 6 5 20 ml of water are added to a solution of 460 mg of 63-4'-tolylsulfonyloxymethylpenicillanic acid in 20 ml of methylene chloride and the pH of the mixture is adjusted. resulting at 6.9 by addition of sodium hydroxide solution. The aqueous phase is separated and the organic phase is further extracted with twice 20 ml of water. After having combined the aqueous phase and the washing liquors, 238 mg of potassium permanganate in 5 ml of water containing 0.16 ml of phosphoric acid are added dropwise. During the reaction period (45 minutes), the pH of the reaction mixture is maintained at 6.0-6.4 by the addition of aqueous sodium hydroxide. The pH of the reaction mixture is then adjusted to 1.5 by addition of 6N hydrochloric acid and 20 ml of ethyl acetate are added. After cooling the mixture to 0 ° C., 460 mg of sodium bisulfite is added all at once. The pH is readjusted to 1.5 by addition of 6N hydrochloric acid and the organic phase is separated, rinsed with saturated sodium chloride solution and dried over magnesium sulfate. By removing the solvent, 300 mg of the product is obtained in the form of a foam.

The NMR spectrum (CDCl3) shows an absorption at 1.45 (s, 3H), 1.65 (s, 3H), 2.45 (s, 3H), 4.4 (m, 3H), 4.42 (s, 1H), 4.8 (d, 1H, J = 4Hz) and 7.6 (ABq, 4H, J = 10Hz) ppm. EXAMPLE 22. Starting from the appropriately selected sulfonyl chloride and the desired benzyl 63-hydroxyalkylpenicillanate * and following the procedure of Example 21, the compounds are prepared. The following: 61 H H ο: 2 v CH-

R, 0-CH * S-Y S

3 i 1 Π CH- R4 J- “-1,„ 0 h- £ 4- î. 'CH3S02- h- (CH3) 2CHS02- h- CH3 (CH2) 3S02 ~ H "ch3so2- ch3- (S) CH3S02" (CH3) 2CHCH2-, (S) CH3CH2S02- C6H5 ”(R) CH3S02- 2'- C5H4N- (S) CH3- (CH2) 2S02- 4'-C5H4N- '(S) c6h5so2- c6h5 (ch2) 2- (S)

CgH5S02- CH3 (CH2) 2- (R) WV · H- 2-.CH3CëH4S ° 2- H ~ '- 4 “Cïï3C5H4S02" CH3- (R) 2- CH3CgH4S02- CH3 (CH2) 3- (R) 3- CH3CgH4S02- CgH5 (CH2) 2- (S) 4- CH3CgH4S02- 3'-C5H4N- (S) 4-CH30CgH4S02- H- 4-CH30CgH4S02- (CH3) 2CH- (S) 3- CH30CgH4S02- C6H5 2- - C2H5 ~ (r) 4- CH3OCgH4SO'2- 4'-C5H4N- (S) 4 2-FCgH4S02- H- 4-FCgH4S02- CH3- (S) 3- FCgH4S02 "(CH3) 3C ~ (R) 4- FCgH4S02- CgH5CH2- (S) 2 »FCgH4S02 ·» 2'-C5H4N- (S) 2-ClC-H.SO-- H- 5 4 2 62 -3- -¾_ 1 2 “C1C6H4S02 ~ · (CH3) 2CHCH2 - (S)

5 4-ClC6H4S02- C6H5CH2 ’M

4-ClC6H4S02- C6H5 (CH2) 2- (R) 4 "C1C6H4S02" 4'-C5H4N- (S) 2- BrCgH4S02- H- 4 “BrC6H4S02- CH3- · (R) 10 4“ BrC6H4S02 'C6H5' (S ) 3- CF3C6H4S02- H- 2 “CF3C6H4S02” C2H5 ~ ^ 4- CF3C6H4S02- H ~ 4 “CF3C6H4S02 ~ CH3" (S)

15 4 “CF3C6H4S02” CßH5CH2 ~ W

4-CF3C6H4SO, - 4? 45h] h- W

20 EXAMPLE 23

6ß-sulfoxymethylpenieillanic acid sulfone A. Pyridinium salt of benzyl ββ-sulfoxymethyl-penicillanate sulfone

860 mg of sulfuric anhydride and pyridine complex are added to a solution of 953 mg of benzyl 63-hydroxymethylpenicillanate sulfone in 75 ml of dimethylacetamide under a nitrogen atmosphere and the reaction mixture is stirred for 45 minutes at room temperature. The mixture is poured with stirring into 30,400 ml of hexane and the new mixture is kept under stirring for 30 minutes. The hexane is poured in by decantation and fresh hexane is added. This operation is repeated several times to obtain 900 mg of the desired product.

35 B. 6B-sulfoxymethylpenicillanic acid sulfone

A mixture of 532 mg of sulfonated pyridinium salt of benzyl 63-sulfoxymethylpenicillanate in 10 ml of water containing 174 mg of sodium bicarbonate is added to a suspension of 500 mg of 10% palladium on charcoal prereduced in 25 ml of water and the resulting mixture is stirred by shaking in a hydrogen atmosphere under pressure of 350 kPa for 1 hour. Another 500 mg of catalyst are added and the reaction is continued for 30 minutes. A final addition of 500 mg of catalyst is carried out and the reduction is continued for 30 minutes. The catalyst is filtered and washed with water. The filtrate and the washing liquors are combined and lyophilized to obtain the crude product which is purified by chromatography on "Sephadex" using water as eluent. The fractions containing the product are combined and lyophilized to give the purified product.

EXAMPLE 24

Starting from the conveniently chosen benzyl 66-hydroxyalkyl-15 penieillanate sulfone and following the operating procedure of parts A and B of Example 23, the following compounds are prepared, which are obtained under the form of their disodium salts.

H H

! I ° 2 CH 3. -. 3 Ni \ 1 H GH- - νμ— -Λ. 1 co2h

Ei_ î CH3— (S) CH3- (R) • ch3ch2- (S) CH3 (CH2) 2- (R) ch3 (ch2) 3- (S) CH3 (CH2) 3- (R) 1 CH3CH (CH3) - (S) (CH3) 3C- (R) ·· '- (CH3) 3C- (S) c6h5- (S) C6H5- (R) C6H5CH2 ~ {S) c6h5 (ch2) 2- (S) C6H3 ( CH2) 2- (R) 2'-C5H4N- (S) 4'-C5H4N- (S) 64 EXAMPLE 25

Pivaloyloxymethyl 63-hydroxymethylpenicillanate sulfone

0.52 ml of chloromethyl pivalate is added to a solution of 1.0 g of sodium salt of 6 $ acid sulfone-hydroxymethylpenicillanic in 10 ml of dimethylformamide, cooled to 0-5 ° C. After stirring for about 16 hours at room temperature, the reaction mixture is poured into a mixture of water and ethyl acetate. The ethyl acetate phase is separated, washed with 3 times 100 ml of water and with 3 times 50 ml of saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo to obtain 1.1 g of the product in the form of an oil.

The NMR spectrum (CDCl 4) shows an absorption at 1.27 (s, 9H), 1.42 (s, 3H), 1.6 (s, 3H), 2.9 (broad s, 1H), 4.2 (m, 3H), 4.58 (s, 1H), 4.75 (m, 1H) and 5.82 (ABq, 2H, 8 ^ -6B = 16Hz) ppm.

EXAMPLE 26 Following the procedure of Example 25 and starting from the 6β-hydroxyalkyl-penicillanic acid sulfone or its suitably chosen derivative and from the desired halide, the following esters are prepared:

H H

/ d: ° 2 / CH3 r3o-ch -'- fs ch3 * 4 cr ~ N - "C02ri 65 —3-— · * 4_— 1 Ri '' · H" H "- -ch (ch3) o2cch3 H" H- - -CH202CCH3 H “H- - -ch (ch3) o2c (ch2) 4ch3 H“ - CH3- (S) -CH202CCH3 H “CH3- (R) -CH202C0CH (CH3) 2 H-” (S) -CH202CC (CH3) 3 H- ~ C6H5 ~ (R) ™ CH202CCH3 h- C6H5- (R) ~ C4H302a H ™ C6H5CH2- (R) -CHjOjCOCH, H- C6H5CH2 “(S) 'C4H5 ° 2b H - C5H5 (CH2) 2- (S) -CH (CH3) 02C0C2H5 Η- CgH5 (CH2) 2- (R) “CgH502c H- 2'-C5H4N- (R) -CH202CCH3 H- 2'-C5H4N- (S ) -CH (CH3) 02C0C2H5 H ~ 3'-C5H4N ~ _ (S) -G (CH3) 202C0 (CH2) 2CH3 H-. 3'-C5H4N-- (R) ~ “-C4H302s H-. '' 3’-C5H4N-. (R) “CH202C0CH3 * H- 4'-C5H4N- '(S) -CH (CH3) 02C (CH2) 4CH3 H- 4'-C5H4N- (S) -C (CH3) 202CC (CH3) 3 H- 4 * -C5H4N- (R) -CH (CH3) 02CCH3

H- 4 * -C5H4N- (R) “CgH502C

ch3co- ch3 (ch2) 2- (r) -ch2o2coch (ch3) 2 CH3CO- (CH3) 2CH2- (S) -CH202CCH3 CH3CO- CgH5 (CH2) 2- (S) -C4H502b CH3CO- 3'-C5H4N- ( S) ~ CH (CH3) 02C0 (CH2) 3CH3 * (CH3) 2CHCO- C2H5 "(S) -CH202C (CH2) 4CH3 ch3 (ch2) 2co- · (CH3) 2CH- (S) -ch (ch3) 02cch3 gh3 (ch2) 2co- g6h5- (S) -ch (ch3) 02cch3 ch3 (ch2) 2co-. 2'-C5H4N- (R) -ch2o2cch3 ch3 (ch2) 2co ~ 4'-c5h4n- (S) -ch2o2cch (ch3) 2 _ CH3 (CH2) 3co- h- - -ch2o2cch3 CH3 (CH2) 3CO- h- ~ -CH (CH3) 02C0 (CH2) 2CH3 r 66 r3_ r4 _; _ i h- (CH3) 2CHCH2CO- CH3 (CH2) 3- (R) -CH202CC (CH3) 3 (CH3) 2CHCH2CO- 2'-C5H4N- (R) "C4H3 ° 2a (CH3) 3CCO- 4'-C5H4N- (S) -ch (ch3) 02cch3 5 CH3 (CH2) 6CO- h- “-C (CH3) 202CC (CH3) 3 CH3 (CH2) 6CO- CgH5CH2- (S) -ch2o2cch3 CH3 (CH2) 6CO- 3'-C5H4N- (S) -CgH502c CH3 (CH2) 9CO- h- - -ch (ch3) 02cch3.

CH3 (CH2) 9CO- h- “-CH (CH3) 02C0C2H5 10 CH3 (CH2) gCO- (CH3) 2CH- (S) -CH202C0CH (CH3) 2 CH3 (CH2) 14C0- h- -" 'CH2 ° 2CCH3 CH3 (CH2) 14CO- h- ”-ch2o2c (ch2) 4ch3 CH3 (CH2) 14C0- ch3- (s) -CH (CH3) 02C0CH3 CH3 (CH2) 14CO- CH3- (S) -C4H502b CH- (CH2) 14C0- 3'-C5H4N- (s) -CH202C0CH3 CH, (CH-) ·. FiC0- H- ”-CH202CC (CH3) 3 CH ^ (CH ^) 15CO- H- - -CH (CH3) 02C0C2H5 ^ a4 -crotonolactonyl Y-butyrolacton-4-yl c3-phthalidyl EXAMPLE 27 6 3 - (, 1- (S) -methylsulfonyloxy-2-phenethyl} -acetoxymethylpenicillanate sulfone

648 mg of chloromethyl acetate are added to a solution of 2.22 g of sodium salt of sulfone of 8- (1- (R) -ethylsulfonyloxybenzylPenicillanic acid in 30 ml of dimethylformamide cooled to 5 ° C. the reaction mixture, with stirring, at ambient temperature for approximately 16 hours, then it is poured into a mixture of water and ethyl acetate, the ethyl acetate phase is separated and rinsed with water and dried over magnesium sulphate. Removing the solvent in vacuo gives the desired product.

67 EXAMPLE 28

The procedure of Example 27 is used, starting from the 6β-sulfonyloxyalkyl-penicillanic acid sulfone and the halide suitably chosen to obtain the following products: ? ° 2 v4CH.

sioj— u — k. i co2 * i —3- * 4- 1 Rx__ CH3S02 ~ H “~ -CH202CCH3 CH3S02" CH3 ~ (S) -CH (CH3) 02C0C2Hs CH3CH2S02 C6H5 "(*) -CH202C0CH3 (CH3) 2CHS02- H- - -C (CH3) 202C0 (CH2) 2CH3 CH3 (CH2) 2S02- 4'-C5H4N- (S) -CH202GC (CH3) 3 CH, (CH -) - S0-- H- - -C (CH,), 0, CC (CH,) -,. ^ 3 <= ΒΗ45θ | - H- - - -CAy 4-CH3C6H4S02- CH3 ”. -. (R) -CH202CCH (CH3) 2 _2-CH30C6H4S02- C2Hs "" (R) -CH (CH3) 02C0CH3 3- CH30C6H4S02- C6H5 "(S) -CH202CCH3 • 4-CH30CgH4S02- 4'-C5H4N- ( ) -CH202CCH3 - 2-FCgH4S02- H- - -CH202CCH3 · '4-FCgH4S02- CH3- (S) -CH202CC (CH3) 3; 2-ClCgH4S02- (CH3) 2CHCH2- (S) -C (CH-j) 202CO (CH2) 2CH3 4- ClCgH4S02- CgH5CH2- (R) -CH ^ CCH-j 4-ClCgH4S02- CgHg (CH2) 2 ~ (R). -CH202C0CH3 2- BrCi, H-S0-- H- - 6 4 2 4 5 2 * 4-BrCgH4S02- CH3 ~ (R) -CgHgO ^ 3- CT3CgH4S02- C2H5- (R) -CCCH3) 202CCH3 4 “CP3C6H4S02 CH3- (S) -CH202C0 (CH2) 2CH3 4- GF3CgH4H2C2 - (S) -CH ^ COCH (CHg) 2

CgH5S02- * CH3 (CH2) 2 "(R) -CH2COCH (CH3) 2 68 —3- —4- 1 h_ C6H5S02“ H "-“ CH202CC (CH3) 3 5 C6H5S02- ÇgH5 (CH2) 2- (S) -CH (CH3) 02CCH3

NaS03- H- - -CH202CCH3

NaS03- CH3 (CH2) 2- (R) -CH (CH3) 02C0C2H5

NaS03- C6H5CH2 ~ (S) -CH202CC (CH3) 3

NaS03- · 21-CgE ^ N- (S) -CH202C0C2H5 10 a4-crotonolactonyl ky-butyrolacton-4-yl c3-phthalidyl 15 EXAMPLE 29

Pivaloyloxymethyl 63-benzoyloxymethylpenicillanate sulfone

900 mg of chloromethyl pivalate is added to a solution of 1.95 g of sodium sulfone salt of 6 8-benzoyloxymethylpenicillanate. in 25 ml of anhydrous dimethylformamide cooled to 0-5 ° C and the mixture is stirred at room temperature for about 16 hours. The mixture is then poured into a mixture of ethyl acetate and water. The ethyl acetate phase is separated, rinsed with water and with a saturated sodium chloride solution and dried over magnesium sulfate. The desired product is obtained by removing the solvent under vacuum.

30 EXAMPLE 30

Starting from the sulfone derivative of 68-hydroxyalkylpenicillanic acid suitably selected in the form of the sodium salt and the desired alkyl halide and using the procedure of Example 29, the following compounds are prepared: : 69 Ο Η Η 0 / Ç ~ \ "* = \ 2 ο '' CH3 \ ι / —C-0-CH SaJ-Y S Nii · CH2 X 4 ο 2- £ 4-; R _ 5 4-Cl - w H - -ch2o2cch3 4 ~ C1 "CH3 ~ (R)“ CH (CH3) 02CCH3 3 ”C1_ (CH3) 3C” <r) -CH-09CC (CH-), 2 — F— rr 4 4 d d H ”-CH (CH3) O2C0C2H5 1Q 4” F "CH3 (CH2) 2 ~ (R) -CH202CC (CH3) 3 3" F ~ 3'-C5H4N-. (R) -C (CH3) 202CCH3 3 "Br ~ (ch3) 2chch2- (S) -c4h3o2 * 4 "Br" C6H5CH2 "(R) -CH202C0CH3 2_CH3" k ^ 3 ^ 2 ^ - (R) -ch (ch3) 02COC2H5 1K 3-CH3- C6H5- (S) -CH20 C (CH) CH-

4 “CH3- H- - -C8H5 ° 2C

4 "CH3" C6H5 (CH2} 2 “(S)” CH2 ° 2C (CH2) 4CH3 4 “CH3“ 4'-C5H4N- (S) ~ C (CH3) 202C0CH3 H ~ 4'-C5H4N- (S) - CH202CCH3

H “CH3 (CH2) 2- (R)“ CH (CH3) 02CCH3 I

2P 4-CF3- · _ 'CH3- - (R) ~ C4ÎI502b 4-CF3: C6H5 (CH2) 2- (S) · -'CH202C0C2H5 3- CH30- CH3 (CH2) 2- (R) -CH202CC (CH3 ) 3 4- CH30- C6H5 "(r) -CH (CH3) 02C0C2H5 4-ch3o- 3'-c5h4n- (S) -c (ch3) 2o2c (ch2) 2ch3 a4-crotonolactonyl y-butyrolacton-4-yle c3 -phthalidyl EXAMPLE 31 "30 6-41-aminobenzoyloxymethylpenicillinate pivaloyloxymethyl sulfone A. 66-4'-nitrobenzoyloxymethylpenicillanate sulfone, pivaloyloxymethyl

1.11 g of 4'-nitrobenzoyl chloride 35 are added to a cold solution (0-5 ° C) of 1.89 g of 66-hydroxymethylpenicillanate sulfone, 0.695 ml of triethylamine and 10 mg of 4-dimethylaminopyridine in 60 ml of methylene chloride under an atmosphere of argon.

70

The resulting reaction mixture is kept under stirring at ambient temperature for 2 hours, then it is extracted with cold water. The organic phase is separated and washed successively with water at pH 1.0, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is then dried over magnesium sulphate and concentrated to dryness under vacuum to obtain the desired intermediate compound.

B. 63-4'-aminobenzoyloxymethylpenicillanate 10 pivaloyloxymethyl sulfone

250 mg of 5% palladium fixed on charcoal is added to a solution of 500 mg of pivaloyloxymethyl 6β-4'-nitrobenzoyloxymethylpenicillanate sulfone in 35 ml of dimethoxyethane and the resulting solution is shaken in an atmosphere of hydrogen at an initial pressure of 210 kPa. After 3 hours, the spent catalyst is filtered and the filtrate is concentrated in vacuo to obtain the desired product.

EXAMPLE 32 Starting from the nitrobenzoyl chloride and the sulfone of ester of 63-hydroxyalkylpenicillanic acid ester suitably chosen and following the procedure of parts A and B of Example 31, the following compounds are prepared:

H H O CH

, __ O:: ° 2 / CH3 rsTCHs a 0J — N -A, ..

NH2 4 U CU2K1 71

Group position

NHn on the nucleus R * R

- ± - —4- - —1- g 2 H- - '4 H- - -CH202C0CH3 2 ch3- (S) -ch2o2cch3 3 (CH3) 2CH- (S) -, CH202CC (CH3) 3 4 - C6H5 " "(R)" C4H3 ° 2a 10 -4 · - C6H5CH2- (S) -C4H502b 4 C, H_ (CH,) - (S) -CH (CH,) 0-C0C2H5.

t ”, -c8h5oV '2 - 2'-C5H4N- (R) -CH202CCH3 4 4'-C5H4N- (S) -CH (CH3) 02C (CH2) 4CH3 15 3 3'-C5H4N (R) -CH202C0CH3 a4- crotonolactonyl y-butyrolacton-4-yle c3-phthalidyl 20 EXAMPLE 33

68-methoxycarbonyloxymethylpenicillanic acid sulfone A. Benzyl 6β-methoxycarbonyloxymethylpenicillanate sulfone 25 0.1 ml of methyl chloroformate and 10 mg of 4-dimethylaminopyridine are added to a solution of 500 mg of benzyl 63-hydroxymethylpenicillanate sulfone 0.196 ml of triethylamine in 20 ml of methylene chloride; cooled to 0 ° C. After stirring for 20 minutes, the solvent is removed under reduced pressure and ethyl acetate is added to the residue. The resulting solid is filtered and the filtrate is washed successively with water, water at pH 1.0, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuo to obtain the desired intermediate compound.

4 72 3f B. 63-methoxycarbonyloxymethylpenicillanic acid sulfone 600 mg of benzyl 63-methoxycarbonyloxymethylpenicillanate sulfone is added to a suspension of 600 mg of 5% palladium fixed on calcium carbonate, prereduced in 20 ml of water with hydrogen under pressure of 350 kPa for 20 minutes. The resulting mixture is stirred by shaking in a hydrogen atmosphere at an initial pressure of 350 kPa for 45 minutes. The catalyst is filtered and washed with a mixture of methanol and water. The filtrate is treated with 75 ml of ethyl acetate and the pH is adjusted to 1.5 by addition of 6N hydrochloric acid. The organic phase is separated, dried over magnesium sulfate and concentrated under empty to get the final product.

15 EXAMPLE 34

Starting from the benzyl 63-hydroxyalkyl penicillanate sulfone and the desired alkyl chloroformate and using the procedures of parts A and B of Example 33, the following compounds are prepared: 73 * * “? ° 2, - = ¾ R30-CH fcj-Ys Y ^ CH3

R4 N "" "C02H

5 s3- 54 — _ i C2H5OCO- CH3- (S) CH30C0- CH3- (R) CH30C0- C2H5 "CH3 (CH2) 2OCO” CH3 (CH2) 2 "(R) 10 (CH3) 2CHOCO- (CH3) 2CH - (S) CH3OCO- CH3 (CH2) 4- (S) CH3 (CH2) 2- (CH3) 3C- (R) CH3OCO C6H5 “(S) C2H5OCO- CgH5CH2- (S) 15 (CH3) 2CHOCO- C6H5CH2- (R) CH3OCO- CgH5 (CH2) 2- (S) CH30C0- 2'-CsH4N- (R) CH30C0- 2'-C5H4N_ (s) 20 C2H5OCO- ': 3 -'- C5H4N- (R) CH (CH2 ) 2OCO-. · · 3'-C5H4N- (S) j C2H5OCO- 4 '”C5H4N- (S) CH3OCO- - 4,” C5H4N- (R) 25 EXAMPLE 35

Sulfone of 6 B-methoxycarbonyloxymethylpenicillanate of acetoxymethyl 30 120 mg of sodium hydride are added to a "solution of 1.6 g of sulfone of 68-methoxycarbonyloxy-methylpenicillanic acid in 20 ml of anhydrous dimethylformamide at 5 ° C. and under an atmosphere After stirring for 10 minutes, 648 mg of chloromethyl acetate are added and the reaction mixture is stirred for about 16 hours at room temperature and the reaction mixture is poured into a mixture of water and ethyl acetate and the organic phase is then separated, rinsed with water and with a saturated solution of 74% sodium chloride and dried over magnesium sulfate. The final product is obtained by elimination solvent in vacuo.

EXAMPLE 36 The procedure of Example 35 is used, starting from the 6β-alkoxycarbonyloxyalkyl-penicillanic acid sulfone and alkyl chloride suitably chosen to obtain the following compounds: 10 HH 02 CH3 R4 JN-1, 0 'CO ^ 15 53—; . s4 —...; Sij_ C2H5OCO- CH3- (5) -CH202CCH3 CH3OCO- C2H5 ~ (R) -CH (CH3) 02CCH3 CH3 (CH2) 20C0- CH3 (CH2) 2- (R) -CH202C0C2H5 (GH3) 2CHQCO- · (CH3) 2CH - - (S) -CH (CH3) 02C0 (CH2) 3CH3 • 20 CH3OCO. ^.-Ch3 (ch2) 4 -. · (S) · "C4H3o2a CH3OCO · - '. .C.h3 (ch2) 4 - · '·. (S) "C (CH-3) 202C0 (CH2) 2CH3 c2h5oco-. c6h5ch2- (S) -ch2o2och3 ch30C0- c6h5 (ch2) 2- (S) -c4H5o2b CH3OCO- 2'-C5H4N- (R) -C8H502 <= C2H5OCO- 3'-C5H4N- (R) -CH (CH3) 02CCH3 C2HsOCO- 3'-C5H4N- - (R) -CH (CH3) 02C0C2Hs C2H5OCO- 4'-C5H4N- (S) -CH202CC (CH3) 3 CH3OCO- 4'-C5H4N- (R) -CH (CH3) 02CCH3 30 a4-crotonolactonyle 'b Y-butyrolacton-4-yle c3-phthalidyl 75 EXAMPLE 37

Benzyl 6 β-methylsulfonyloxymethylpenicillanic acid A. 68-methylsulfonyloxymethylpenicillanate

194 mg of methylsulfonyl chloride are added to a cooled solution (-10 ° C.) of 800 mg of benzyl 6β-hydroxymethyl penicillanate and 0.55 ml of triethylamine in 25 ml of methylene chloride. After stirring for 1 hour, the reaction mixture is washed successively with water, water at a pH equal to 1.0, a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and evaporated to dryness to obtain 650 mg of the desired product.

B. 6β-methylsulfonyloxymethylpenicillanic acid 15 300 mg of benzyl 6 8-methylsulfonyloxymethylpenicillanate are added to a 300 mg suspension of 5% palladium fixed on calcium carbonate, prereduced with hydrogen under pressure of 329 kPa for 15 minutes in 20 ml of a mixture of methanol and water at 1: 1 and the reduction is continued for 30 minutes at 329 kPa. A further 300 mg of catalyst is added, and the reduction is continued for a further 30 minutes. The spent catalyst is filtered and the methanol is removed from the filtrate under vacuum. The aqueous residue is extracted with ethyl acetate and the pH of the aqueous phase is adjusted to 2 by addition of 6N hydrochloric acid. The acidified aqueous phase is extracted with fresh ethyl acetate and separates the organic phase, then rinses it with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and evaporated to give 269 mg of the desired product as an oil.

The NMR spectrum (CDCl 4) shows an absorption at 1.56 (s, 3H), 1.68 (s, 3H), 3.06 '(s, 3H), 4.1 (m, 1H), 4 , 41 (s, 1H), 4.52 (m, 2H), 5.47 (d, 1H, J = 4Hz) and 8.3 (s, 35 1H) ppm.

EXAMPLE 38

Starting from the sulfonyl chloride and the benzyl 6 8-hydroxymethylpenicillanate suitably chosen and following the procedure of Example 37, the following compounds are prepared:! ί - '

H H

: * P * 3 ·

:: s ν 'J

R ..... ^ CH3

5 0 y # C02H

R

(CH3) 2CHS020CH2- CH3 (CH2) 3S02OCH2- 10 CgH5S020CH2- 2-CH3C6H4S020CH2- 4-CH30CgH4S020CH2-

2-FCgH4S02OCH2- J

2- ClCgH4S020CH2- 15 2-BrCgH4S02OCH2- 3- CF3CgH4S020CH2- 4- cF3cgH4S ° 2OCH2- 20 EXAMPLE 39

6 ß- C1- (S) -hydroxy-3-phenylpropylacidicillanic acid

Add 244 mg of benzyl 68- (1- (S) -hydroxy-3-phenyl-propyljpenicillanate (Example 11, part B) to a suspension of 244 mg of 5% palladium fixed on calcium carbonate, pre-reduced with hydrogen under pressure of 350 kPa for 20 minutes, in 20 ml of mixture of methanol and water at 1: 1, and the resulting mixture is shaken by shaking in a hydrogen atmosphere at an initial pressure of 364 kPa for 1 hour At this point, a further 244 mg of catalyst is added and the hydrogenation is continued for 1 hour, 244 mg of catalyst are added again and the reduction is completed in 1 hour. the methanol is removed in vacuo, the aqueous residue is extracted with ethyl acetate and then acidified to a pH of 1.8 by addition of 6N hydrochloric acid. The acidified aqueous phase is extracted with fresh ethyl acetate, and the organic phase is separated, rinsed with saturated sodium chloride solution and dried te on 77 magnesium sulfate. By removing the solvent under reduced pressure, 127 mg of the desired product are obtained, melting at 135-137.5 ° C.

The NMR spectrum (CDCl 4, DMSO-dg) shows absorption at 1.57 (s, 3H), 1.59 (s, 3H), 1.8 (m, 2H), 2.8 (m, 2H), 3.6 (d, d, J = 10, 4Hz), 4.0 (m, 1H), 4.13 (s, 1H), 5.4 (d, 1H, J = 4Hz) and 7 , 2 (s, 5H) ppm.

EXAMPLE 40

6 ß- [1- (R) -hydroxy-3-phenylpropyl) penicillanic acid 10 369 mg of benzyl 6ß- [1- (R) -hydroxy-3-phenylpropylpenicillanate (Example 11, part B) are added to a suspension of 369 mg of 5% palladium fixed on calcium carbonate, prereduced with hydrogen under pressure of 364 kPa for 20 minutes, in 20 ml of a mixture of methanol 15 and water at 1: 1, and the resulting mixture is stirred by shaking in a hydrogen atmosphere under pressure of 364 kPa for 1 hour. Three 370 mg portions of the catalyst are added every hour for 3 hours, then hydrogen under pressure of 364 kPa. One hour after the last addition, the catalyst is filtered and the methanol is removed from the filtrate. · The aqueous residue is extracted with ethyl acetate, then it is acidified to a pH equal to 1.5 by addition of 6N hydrochloric acid. Fresh ethyl acetate is added to the phase acidified aqueous solution and the organic phase is separated, washed with saturated sodium chloride solution and dried over magnesium sulfate. By removing the solvent in vacuo, 110 mg of the desired product is obtained, melting at 131-135 ° C.

The NMR spectrum (CDCl 4, DMSO-dg) shows absorption at 1.53 (s, 3H), 1.65 (s, 3H), 1.8 (m, 2H), 2.8 (m , 2H), 3.5 (d, d, J = 9.4Hz), 4.1 (m, 1H), 4.3 (s, 1H), 5.3 (d,. 1H, J-4Hz) and 7.3 (s, 5H) ppm.

EXAMPLE 41 6 pivaloyloxymethyl pivaloyloxymethyl b-methylsulfonyloxymethylpenicillanate

0.53 ml of chloromethyl pivalate is added to a solution of 1.0 g of sodium salt of 6 8-methyl-sulfonyloxymethylpenicillanic acid in 10 ml of dimethylformamide cooled to 0-5 ° C, and the resulting reaction mixture with stirring at room temperature for about 16 hours. The mixture is poured into a mixture of water and ethyl acetate, and the organic phase is separated, rinsed with saturated sodium chloride solution and dried over magnesium sulfate. By removing the solvent in vacuo, the desired product is obtained. EXAMPLE 42

Starting from the suitably chosen penicillanic acid and the desired halide, and following the procedure of Example 41, the following compounds are prepared: H Ξ Ξ: o ch3

- * NOT

R "T fSNf * ca3 '0 N_ \ C ° 2K1 i 79 j" 5 CH3S020CH2- -CH (CH3) 02CCH3 CH3S020CH2-. -CH202CCH3 CH3S020CH2- -CH202C0CH (CH3) 2 (CH3) 2CHS020CH2- -CH202CHCH2C3 - · -CH202C0CH3 (CH3) 2CHS020CH2- -C4H302a (CH3) 2CHS020CH2- -C (CH3) 202CC (CH3) 3 CH3 (CH2) 3S020CH2- -CH (CH3) 02C0 (CH2) 3CH3 CH3 (CH2) 3S020CH2-3CH2 CH3 (CH2) 3S020CH2- -C4H502b C, HcCO-OCHn- -CH, 0 to 6 5 2 2 4 3 2

CgH5S020CH2- -CH (CH3) 02C0C2H5 C6H5S020CH2- -CH202C (CH2) 4CH3 2-CH3CgH4S020CH2- -CH ^ CC (CH3) 3 2-CH3CgH4S020CH2- -CH (CH3) 02CCH3 2-CH3CgH4S030CH2- '-CH (CH 3) • 02C0C2H5 4-CH30CgH4S020CH2 ~ 2-FCgH4S020CH2-. -CH202C (CH2) 4CH3 2-FCgH4S020CH2- -C (CH3) 2 ° 2CO (CH2 ^ 2CH3 2-ClCgH4SO20CH2- -CH202C0CH (CH3) 2 2-ClCgH4S020CH2- -CH202CCH3 2-ClCgH4SCH202 - -C4H302a 2-BrCgH4S020CH2- - '-C4H502b 2-BrCgH4S02QCH2- - -CH202CCH3 2-BrCgH4S020CH2- -CH202C0CH3 / i 80, RR ^ _ .3-CF3CgH4S020CE2- -CH ^ CC. SO-OCH., - -CH = 0ob 36 422 452 4- cf3c6h4so2och2- -c cch3) 2o2cc (ch3) 3 4-CF3CgH4S02OCH2- -CH202CCH3

4-cf3c6h4so2och2- -ch (ch3) o2co (ch2) 3ch3 I

(S) cgH5 (ch2) 2choh- -ch2o2cch3 J

(S) ÇgH5 (CH2) 2CHOH- -CH (CH302C0C2H5 (S) CgH5 (CH2) 2CHOH- -CH202C (CH2) 4CH3

(R) CgH5 (CH2) 2CHOH- -CgH502C

(R) CgH5 (CH2) 2CHOH- -C (CH3) 202C0 (CH2) 2CH3 (R) CgHs (CH2) 2CHOH- -CH202C0CH (CH3) 2 î

Claims (17)

1 H - \, fo / '' co2ch2c6h5 ~: - ^ w in which Y and n have the definitions given above, provided that when Y represents R, n is 0 and that when Y represents R £, is equal to 2 and, where appropriate, form a pharmaceutically acceptable base salt of this compound. 1. R.-CH-4 ^ in which R ^ is chosen from a sulfo group, a hydrogen atom, an alkoxycarbonyl group having 2 to 4 atoms of r-. carbon, an alkanoyl group having 2 to 18 carbon atoms, a benzoyl group, a substituted benzoyl group the substituent of which is chosen from an amino group, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom and a trifluoromethyl group, an alkylsulfonyl group having 1 to 4 carbon atoms, a phenylsulfonyl group and a substituted phenylsulfonyl group the substituent of which is chosen from - 2 - f while is chosen from the group comprising a hydrogen atom an alkyl group having 1 to 4 carbon atoms, a phenyl group, a pyridyl group, a benzyl group and a β-phenethyl group; is chosen from the group comprising a hydrogen atom and ester-forming radicals which are easily hydrolysable in vivo. 2 * Pharmaceutical composition according to claim 1, characterized in that R ,. is chosen from the group comprising a hydrogen atom and ester-forming radicals easily hydrolyzable in vivo chosen from an alkanoyloxymethyl group having, 3 to 6 carbon atoms, a 1- (alkanoyloxy) -ethyl group having 4 to 7 atoms carbon, an m 1-methyl-1- (alkanoyloxy) -ethyl group having 5 to 8 carbon atoms, an alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms a 1- (alkoxycarbonyloxy) -ethyl group having 4 to 7 carbon atoms carbon, a 1-methyl-1- (alkoxycarbonyloxy) ethyl group having 5 to 8 carbon atoms, a 3-phthalidyl group, a 4-crotonolactonyl group and a Y-butyrolacton-4-yl group. 1 · Pharmaceutical composition intended for the treatment of bacterial infections in mammals, characterized in that it comprises a pharmaceutically acceptable carrier, an antibiotic of the ß-lactam type and a. compound corresponding to one of the formulas: HH HH ° 2 r> ch3 · J — n — l 3 d—— 0 * "C02R5 é C02R5 III and IV (or a pharmaceutically acceptable base salt of this compound ), formulas in which R is chosen from an alkylsulfonyloxymethyl group having 1 to 4 carbon atoms in its alkyl group, a phenylsulfonyloxymethyl group, a substituted phenylsulfonyloxymethyl group whose substituent is chosen from a methyl group, a methoxy group, a fluorine atom , a chlorine atom, a bromine atom and a trifluoromethyl group, as well as an 1-hydroxy-3-phenylpropyl group; R2 is a group of formula: 0-R. 3 · Pharmaceutical composition according to claim 2, characterized in that the β-lactam antibiotic is chosen from the group of following compounds: 6- (2-phenylacetamido) penicillanic acid, * 6- (2- phenoxyacetamido) penicillanic,> 6- (2-phenylpropionamido) penicillanic acid, 6 (D-2-amino-2-phenylacetamido) penicillanic acid,. Penicillanic 6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) acid "penicillinic 6- (D -2-amino-2- [1,4-cyclohexadienyl] acetamido) acid '6- (l-aminocyclohexane-carboxamido) penicillanic acid, 6- (2-carboxy-2-phenylacetamido) penicillanic acid, •' - 3 - ir 11 acid 6- (D-2- [4-ethylpiperazin-2 , 3 “dione-l-carboxamido] -2-phenylacetamido) penicillanic acid 6- (D-2- [4-hydroxy-1,5-naphthyridine-3-carboxamido] -2-phenylacetamido) -penicillanic 6- (D-2-sulfo-2-phenylacetamido) penicillanic acid, 6— (D-2-sulfamino -2-phenylacetamido) penicillanic acid, 6- (D-2- [imidazolidin-2- one-l-carboxamido] -2-phenyl- ", acetamido) penicillanic acid 6- (D-2- [3-methylsulfonylimidazolidin-2-one-l-carboxamido 2-phenylacetamido) penicillanic acid, 1. acid 6- ([hexahydro-1H? -azepin-1-yl] methylene-amino) penicillani that, acetoxymethyl 6- (2-phenylacetamido), penicillanate, 6- (D-2-amino-2-phenylacetamido) penicillanate acetoxymethyl 6- (D-2-amino-2- [4-hydroxyphenyl] acé tamido) acetoxymethyl penicillanate, pivaloyloxymethyl penicillanate 6- (2-phenylacetamido) pivaloyloxymethyl penicillanate 6- (D-2-amino-2-phenylacetamido) <<6- (D-2-amino-2) - [4-hydroxyphenyl] acetamido) pivaloyloxymethyl penicillanate, 1- (ethoxycarbonyloxy) - * ethyl (6- (2-phenylacetamido) penicillanate! »V * 1- (D-2-amino-2-phenylacetamido) penicillanate ethyl, 1- (D-2-amino-2- [4-hydroxyphenyl] acetamido) penicillanate - (ethoxycarbonyloxy) ethyl, 6- (2-phenylacetamido) 3 ~ phthalidyl penicillanate, 6- (D-2-amino-2-phenylacetamido) 3-phthalidyl penicillanate 6- (D-2-amino-2 - '- 4 - 1 * 6- (2-phenoxycarbonyl-2-phenylaeetamido) penicillanic acid, 1 - 6- (2-tolyloxycarbonyl-2-phenylacetamido) penicillanic acid, 6- (2- [5-indanyloxycarbonyl] -2-phenylacetamido) penicillin, 1 * 6- (2-phenoxycarbonyl-2- [3-thienyl] acetamido) penicillanic acid, 6- (2-tolyloxycarbonyl- 2- [3-thienyl] acetamido) penicillani-que,. 11 6- (2- [5-indanyloxycarbonyl] -2- [3-thienyl] acetamido) penicillanic acid, 6- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) acid penicillinic, 7- (2- [2-thienyl] acetamido) cephalosporanic acid, 11 7- (2- [1-tetrazolyl] acetamido-3- (2- [5-methyl-l, 3> 4) acid -thia-diazolyl] thiomethyl) -3-deacetoxymethyl-cephalosporanic acid 7- (D-2-formyloxy-2-phenylacetamido) -3- (5- [1-methyltetra-zolyl] thiomethyl) -3-d® sacetoxymethyl-cephalosporanic, 7- (D-2-amino-2-phenylacetamido) deacetoxy-cephalosporanic acid, 7-cc-methoxy-7- (2- [2-thienyl] acetamido) acid -3 ~ carb amoyloxy-methyl-3-deacetoxymethyl-cephalosporanic, 7- (2- cyanacetamido) cephalosporanic acid, 7- (D-2-hydroxy-2-phenylacetamido) -3- (5- [1-methyltetra- »Zolyl] thiomethyl) -3-deacetoxymethyl-cephalosporanic,» acid 7- (b-2-amino-2-p-hydroxyphenylacetamido) deacetoxy-cephalosporanic, acid 7 “(2- [4“ pyridylthio] acetamido) cephalosporanic, J- (D-2-amino-2 [1,4-cyclohexadienyl] acetam acid ido) cephalosporanic, 1. 7- (D-2-amino-2-phenylacetamido) cephalosporanic acid, 1. 7-ΓD acid - (-) - a- (4-ethyl-2,3-dioxo-l- piperazine-carboxamido) - f '- 5 - 7 “acid (D-2-amino-2-phenylacetamido) -3-chloro-3-cephem-4-carboxylic acid, 7- [2- (2- amino-4-thiazolyl) -2- (methoximino) acetamido] -cephalosporanic, [6R, 7R-3-carbamoyloxymethyl-7 (2Z) -2-methoxyimino (fur-2-yl) -acetamido-ceph-3-em -4-carboxylate], 7 * "acid [2- (2-aminothiazol-4-yl) acetamido] -3- [", 2-dimethyl-aminoethyl) -lH-tetrazol-5-yl] thio) methyl ] ceph-3 ~ em-4-carboxylic acid, as well as their pharmaceutically acceptable salts, 4. Pharmaceutical composition according to claim 3, characterized in that the compound corresponds to formula (IV) in which Rj. is a hydrogen atom, 3 * 5 · Pharmaceutical composition according to claim 4} characterized in that R ^ and R ^ each represent a hydrogen atom, 6, A pharmaceutical composition according to claim 4f characterized in that R ^ represents an acetyl group and R ^ represents a hydrogen atom, 7 · Pharmaceutical composition according to claim 4j characterized in that R ^ represents a stearoyl group and R ^ represents a hydrogen atom. 8, Pharmaceutical composition according to claim 4 ^? characterized in that R ^ represents a benzoyl group and R ^ represents a hydrogen atom. VS 9 »Pharmaceutical composition according to claim 4, characterized in that R ^ represents a hydrogen atom and R ^ represents a methyl group, 10. Pharmaceutical composition according to claim 3f characterized in that the compound corresponds to formula (XIl) in which R ^ is a hydrogen atom. 11. Pharmaceutical composition according to claim- Τ · -6. 12. Pharmaceutical composition according to claim 10, characterized in that R represents a p-toluene sulfonyloxymethyl group. 13 · Pharmaceutical composition according to claim 10, characterized in that R represents a 1-hydroxj 3-phenylpropyl group. 14 · Process for the preparation of a compound corresponding to the formula: ^ (°) nx HH n CH- 'x - - -c 3 r * TX Ί ^ -εΗ3 -ko ^' / C02H (or a salt of pharmaceutically acceptable base of this compound), formula in which Y represents R or R2, R representing a 1-hydroxy-3-phenylpropyl group, an alkylsulfonyloxymethyl group having 1 to 4 carbon atoms in the alkyl group, a group substituted phenylsulfonyloxymethyl or a substituted phenylsulfonyloxymethyl group the substituent of which is a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom or a trifluoromethyl group R2 is a group of formula: 0-R- * '0. * R.-CH- 4 _ * in which R is a sulfo group, a hydrogen atom, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkanoyl group having 2 to 18 carbon atoms, a benzoyl group, a phenylsulfonyl group, or a benzoyl group or a substituted phenylsulfonyl group, the substituent of which is a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom or a trifluoromethyl group; Ψ '- 7 - R ^ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group or a phenethyl group and n is. equal to 0 or 2, characterized in that it consists in eliminating a benzyl group from a compound of formula; H H <°> n 15 · A method according to claim 14 * characterized in that the benzyl group is removed by hydrogenation in the presence of a palladium catalyst in a solvent inert to the reaction. 16. Process for the preparation of a compound of formula: HH ^ n ** '* C02Z ^ * in which Y represents R or R £, R representing a group ^ 1-hydroxy-3-phenylpropyl, an alkylsulfonyloxymethyl group r having 1 with 4 carbon atoms in the alkyl group, a phenylsulfonyloxymethyl group or a substituted phenylsulfonyloxymethyl group the substituent of which is a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom or a trifluoromethyl group; R ^ is a group of formula:? -R3 R.-CH- ^ '- 8 - pT * s in which R ^ is a sulfo group, a hydrogen atom, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkanoyl group having 2 to 18 carbon atoms, a benzoyl group, a phenylsulfonyl group or also a substituted benzoyl or phenyl-sulfonyl group the substituent of which is a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom or a trifluoromethyl group $ represents a hydrogen atom, an alkyl group having 1 to 4 atoms. > carbon, a phenyl group, a benzyl group or a \ V ”group * phenethyl j Z represents an ester-forming radical which is easily hydrolysable in vivo, while n is equal to 0 or 2, characterized in that it consists of reacting the base salt of a compound of formula: (0) n Tfcji ÎLs ^.> '' ,, ch3 ^ 1-y γ — ch3 -N-1 /, 0 ^ '' / C02H in which Y and n have the definitions given above, with a compound of formula: XZ in which Z has the definition given above and X is a halogen atom, provided that, when Y represents R, ni is equal to 0 and that, when Y represents R9, n is equal to 2, ^ i 17 · A method according to claim 16, characterized U in that the ester-forming radicals easily hydrolyzable in vivo are alkanoyloxymethyl groups having 3 to 6 carbon atoms, 1- (alkoyoyloxy) ethyl having 4 to 7 carbon atoms, l -methyl-l- (alkanoyloxy) ethyl having 5 to 8 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1— (alkoxy carbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-l- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, 3-phta-